Acute Myeloid Leukemia, FLT3-mutated Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Cytarabine, Idarubicin, ASP2215
Brief summary
The purpose of phase 1 part in this study was to determine the maximum tolerated dose (MTD) and/or recommended expansion dose (RED) of ASP2215 concomitant with cytarabine/idarubicin as induction chemotherapy based on the status of the onset of dose-limiting toxicity (DLT) in newly diagnosed Acute Myeloid Leukemia (AML) subjects. Phase 1 part also evaluated safety and tolerability and characterized the pharmacokinetic (PK) parameters of ASP2215 concomitant with induction and consolidation chemotherapy as well as evaluated the PK parameters of cytarabine concomitant with ASP2215. The purpose of phase 2 part was to evaluate efficacy of ASP2215 in combination with induction therapy. Phase 2 cohort also evaluated safety and characterized the PK parameters of ASP2215 in combination with induction and consolidation therapy followed by maintenance therapy in newly diagnosed FLT3-mutated AML subjects.
Detailed description
This study was composed of Phase 1 part (the dose-evaluation part and the expansion part) and Phase 2 part. In the dose-evaluation part of Phase 1 part, at least 3 subjects received ASP2215 at each dose (low, middle, and high) for determination of MTD and/or RED. Treatment of AML in Phase 1 part was composed of 3 periods of therapy: remission induction, consolidation, and maintenance. The decision of whether or not to proceed to the next dose was made based on the occurrence of DLT during Cycle 1 of the induction period. In the expansion part of Phase 1 part, a maximum of 3 subjects received ASP2215 at RED that had been recommended in the dose-evaluation part and the safety was assessed based on the onset of DLTs during Cycle 1 of the induction and consolidation periods. In Phase 2 part, Subjects received ASP2215 at the recommended dose established in Phase 1 part. The target population was limited to newly diagnosed FLT3-mutated AML.
Interventions
DRUGGilteritinib
Once-daily oral administration on 14 consecutive days in every cycle in each period.
DRUGIdarubicin
Induction period: Once-daily intravenous injection of 12 mg/m\^2 idarubicin on 3 consecutive days.
DRUGCytarabine
Induction period: Once-daily intravenous injection of 100 mg/m\^2 cytarabine on 7 consecutive days. Consolidation period: Twice-daily intravenous injection of 1.5 g/m\^2 cytarabine on Days 1, 3, and 5.
Sponsors
Astellas Pharma Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 69 Years
Healthy volunteers
No
Inclusion criteria
\[Phase 1 part\] * Subject is defined as having previously untreated de novo AML according to the World Health Organization (WHO) criteria (2008) within 28 days prior to study enrollment. * Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. * Subject must meet all of the following criteria in the laboratory test at screening: * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels of ≤ 2.5 × institutional upper limit of normal (ULN) * Total serum bilirubin level of ≤ 1.5 × institutional ULN * Serum creatinine level of ≤ 1.5 × institutional ULN or an estimated glomerular filtration rate (eGFR) of \> 50 mL/min * Subject is suitable for oral administration of ASP2215. * Female subject falls under the following: * Of non-childbearing potential: * ・Post-menopausal (defined as at least 1 year with no menses without a medical reason such as drug administration) at screening, or * ・Documented surgically sterile or status post-hysterectomy (at least 1 month prior to screening) * Of childbearing potential: * ・Has a negative result for the pregnancy test at screening, and * ・Agrees to use an appropriate contraception starting at screening and throughout the study period and for 60 days after the final study drug administration * Female subject agrees not to breastfeed starting at screening and throughout the study period and for 60 days after the final study drug administration. * Female subject agrees not to donate ova starting at screening and throughout the study period and for 60 days after the final study drug administration. * Male subject and his female spouse/partner who is of childbearing potential agrees to use an appropriate contraception starting at screening and throughout the study period and for 120 days after the final study drug administration. * Male subject agrees not to donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration. * Subject agrees not to participate in another interventional study while on study treatment. * Subject can be admitted during the induction period. \[Phase 2 part\] * Subject has a diagnosis of previously-untreated de novo acute myeloid leukemia (AML) according to World Health Organization (WHO) classification (2017) documented within 28 days prior to enrollment. * Subject is positive for FLT3-ITD and/or TKD mutation in bone marrow or whole blood as determined by the central lab. Registration by the local lab result is not acceptable. * Subject has an ECOG performance status (PS) 0 to 1. Subject who has an ECOG PS 2 is eligible only if the primary disease related symptoms such as pneumonia and febrile neutropenia are the cause of PS score. * Subject is suitable for oral administration of ASP2215. * Female subject is not pregnant and at least 1 of the following conditions apply: * Not a woman of childbearing potential (WOCBP) * WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 180 days after final study treatment administration. * Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration. * Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration. * Male subject and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 120 days after the final study drug administration. * Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration. * Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 120 days after the final study treatment administration. * Subject agrees not to participate in another interventional study while on treatment. * Subject must meet the following criteria as indicated on the clinical laboratory tests: * Serum creatinine ≤ 1.5 × institutional upper limit of normal (ULN), or if serum creatinine outside normal range, then glomerular filtration rate (GFR) \> 50 mL/min/1.73m\^2 as calculated with the 4-parameter Modification of Diet in Renal Disease (MDRD) equation. * Serum total bilirubin ≤ 2.5 mg/dL (43 μmol/L), except for subjects with Gilbert's syndrome. * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x ULN. If liver abnormality by the primary disease is suspected, subject may be pre-registered to initiate the chemotherapy. Prior to registration, AST/ALT values must meet the criteria to continue the study. * Serum magnesium ≥ institutional lower limit of normal (LLN). Subject may pre-register without magnesium value, but subject must meet the criteria prior to the full registration on Day 8. * Serum potassium ≥ institutional lower limit of normal (LLN).
Exclusion criteria
\[Phase 1 part\] * Subject was diagnosed with acute promyelocytic leukemia (APL). * Subject has breakpoint cluster region-abelson (BCR-ABL)-positive leukemia (chronic myelogenous leukemia in blast crisis). * Subject has active malignant tumors other than AML or myelodysplastic syndrome (MDS). * Subject has received prior AML treatment except for the following: * Urgent leukapheresis * Hydroxyurea administration for emergency treatment of hyperleukocytosis (≤ 7 days) * Administration of retinoic acid before the diagnosis to exclude APL (≤ 7 days) * Supportive care using growth factors or cytokines * Steroid administration to treat hypersensitivity or blood transfusion reactions * Subject has clinically active central nervous system leukemia. * Subject has disseminated intravascular coagulation (DIC). * Subject has had major surgery within 28 days prior to the first study drug administration. * Subject has had radiation therapy within 28 days prior to the first study drug administration. * Subject has congestive heart failure of New York Heart Association (NYHA) class 3 or 4, or subject with a past history of congestive heart failure of NYHA class 3 or 4 and in whom echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of \< 45%. * Subject has cardiac impairment or a clinically significant cardiac disease, including any one of the following: * Complete left bundle branch block * Obligate use of a cardiac pacemaker * Long QT syndrome at Screening * Prolongation of the QTc interval (\> 450 ms) on electrocardiogram (ECG) at screening * Right bundle branch block + left anterior hemiblock (bifascicular block) * Angina pectoris within 3 months prior to study drug administration * Acute myocardial infarction within 3 months prior to study drug administration * Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A. * Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject. * Subject requires treatment with concomitant drugs that target serotonin 5HT1 or 5HT2B receptors or sigma receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject. * Subject has an active uncontrollable infection. * Subject is known to have human immunodeficiency virus (HIV) infection. * Subject has active hepatitis B or C or other active hepatic disorders. * Subject has any condition that, in the investigator's or sub-investigator's opinion, makes the subject unsuitable for study participation. * Potassium and magnesium levels of below institutional lower limit of normal in the laboratory test at screening. \[Phase 2 part\] * Subject was diagnosed with acute promyelocytic leukemia (APL). * Subject has known BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). * Subject has therapy-related AML. * Subject has active malignant tumors other than AML. * Subject has received previous therapy for AML, with the exception of the following: * Emergency leukapheresis * Emergency treatment for hyperleukocytosis with hydroxyurea for ≤ 10 days * Preemptive treatment with retinoic acid prior to exclusion of APL ≤ 7 days * Growth factor or cytokine support * Steroids for the treatment of hypersensitivity or transfusion reactions. * Subject has QTcF interval \> 450 ms (average of triplicate determinations based on central reading). * Subject with long QT syndrome. * Subject has clinically active central nervous system leukemia. * Subject has had major surgery within 4 weeks prior to the first study dose. * Subject has radiation therapy within 4 weeks prior to the first study dose. * Subject has immediate life-threatening, severe complications of leukemia such as severe uncontrolled bleeding and/or severe disseminated intravascular coagulation * Subject is known to have human immunodeficiency virus infection. * Subject has active hepatitis B or C. * Subject has an uncontrolled infection. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed. * Subject has uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of acute ischemia, congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject has a history of congestive heart failure of NYHA class 3 or 4 and echocardiogram (ECHO) or Multiple Gate Acquisition (MUGA) scan performed within 3 months prior to screening or at screening showed a left ventricular ejection fraction (LVEF) of \< 45%. * Subject requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A. * Subject requires treatment with concomitant drugs that target serotonin 5HT2B receptors or sigma nonspecific receptors, with the exception of drugs that are considered absolutely essential for treatment of the subject. * Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject. * Subject has prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent \< 5 years previously will not be allowed. * Subject has any condition which makes the subject unsuitable for study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib | Day 1 up to the end of Induction period cycle 1 (up to 42 days) | The MTD was defined as the highest dose of gilteritinib at which the posterior mean of the DLT incidence during Cycle 1 of induction therapy was estimated to be closest to 33%. |
| Phase 1 Part: Recommended Expansion Dose (RED) of Gilteritinib | Day 1 up to the end of Induction period cycle 1 (up to 42 days) | RED was the recommended dose used in Phase 2 of the study that was decided by the sponsor's responsible person by comprehensively assessing the data obtained from the study. |
| Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib | Day 1 up to the end of Consolidation Cycle 1 (approximately up to 4 months) | DLTs were defined as: Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: * Anorexia or fatigue * Grade 3 nausea and/or vomiting if participant did not require tube feeding or total parenteral nutrition, or diarrhea if the events did not require or prolong hospitalization that could be managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset. * Grade 3 mucositis that resolved to Grade ≤ 2 within 7 days of onset, fever with neutropenia, with or without infection, infection * Grade 4 peripheral neutrophil count \< 500/cubic millimeters (mm\^3) * Platelet count \< 20,000/mm\^3 due to bone marrow hypoplasia * Grade ≥ 3 platelet count \< 50,000/mm\^3 accompanying bleeding * Grade 4 platelet count \< 25,000/mm\^3 requiring platelet transfusion DLT was assessed until cycle 1 of dose evaluation induction period and until cycle 1 of dose expansion consolidation period. |
| Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.1 years) | An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE included both serious and non-serious AEs. TEAE for Phase 1 was defined as an AE observed after the date of first dose until 30 days after the last dose. |
| Phase 2 Part: Complete Remission (CR) Rate: Induction Period | From the date of first dose up to the start of Consolidation (approximately up to 4 months) | Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Predose on Cycle 1 Day 1, 3, and 8 Consolidation period: Predose on Cycle 1 Day 2 and 6 | Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated. |
| Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period : Predose on Cycle 1 Day 15 and 21 Consolidation period: Predose on Cycle 1 Day 8 and 15 | Ctrough is the plasma concentration prior to drug administration. |
| Phase 2 Part: Overall Survival (OS) | From the date of first dose up to the date of death (maximum duration: approximately 4.4 years) | Overall survival (OS) was defined as the time from the date of first dose of day 1 to the date of death due to any cause. Participants still alive or lost to follow up was censored at the time they were last known to be alive. Kaplan-Meier (KM) estimate was used for analysis. |
| Phase 2 Part: Event Free Survival (EFS) | From the date of first dose up to the date of documented relapse, treatment failure or death from any cause (maximum duration: approximately 4.4 years) | Event-free survival (EFS): time from date of first dose of study regimen until date of documented relapse, treatment failure or death from any cause, whichever occurred first. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. Treatment failure: participants who failed to achieve composite complete remission (CRc) or who discontinued treatment due to lack of efficacy without previous response. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: defined in outcome measure #5. |
| Phase 2 Part: Relapse Free Survival (RFS) | From the date of achievement of first CRc up to the date of documented relapse or death from any cause (maximum duration: approximately 3.9 years) | Relapse-free survival (RFS): time from date of achievement of first CRc until relapse or death from any cause. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. |
| Phase 2 Part: CR Rate After Consolidation and Maintenance Period | CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years) | Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the consolidation period refers to the best response from the start of treatment in the induction period until the end of the consolidation period and for the maintenance period refers to the best response from the start of treatment in the induction period until the end of the maintenance period. |
| Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period | IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years) | CR% without MRD reported. CR rate without MRD after each treatment therapy was defined similarly as CR rate after each treatment therapy. Responders achieve that the best response is CR and MRD status was negative. CR was defined as a morphologically leukemia-free state, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP. |
| Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period | IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years) | Percentage of participants with CRh was reported. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP. |
| Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1 | Cmax was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated. |
| Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period | IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years) | Percentage of participants with CR/CRh was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP. |
| Phase 2 Part: Duration of CR | From the date of achieving CR up to the date of documented relapse (maximum duration: approximately 2.6 years) | Duration of CR was defined as the time from the date of achieving first CR until the date of first documented relapse for participants who achieved CR. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. |
| Phase 2 Part: Duration of CR/CRh | From the date of achieving CR/CRh up to the date of documented relapse (maximum duration: approximately 2.6 years) | Duration of CR/CRh is defined as the time from the date of achieving first CR/CRh until the date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. |
| Phase 2 Part: Duration of CRh | From the date of achieving CRh up to the date of documented relapse (maximum duration: approximately 2.6 years) | Duration of CRh was defined as the time from date of achieving first CRh until date of first documented relapse for participants who achieved CRh. KM estimate was used for analysis. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. |
| Phase 2 Part: Duration of CRc | From the date of achieving CRc up to the date of documented relapse (maximum duration: approximately 2.7 years) | Duration of CRc is defined as the time from the date of achieving first CRc until the date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. |
| Phase 2 Part: Duration of Response (DoR) | From the date of achieving CR, CRp, CRi/PR up to the date of documented relapse (maximum duration: approximately 2.7 years) | DoR: from first day of achieving CRc (CR+ CRp,+CRi)/partial remission (PR) to first day of relapse. KM estimate was used for analysis. CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 & platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Peripheral blood blast counts was ≤ 2%. CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). PR: condition with regeneration of normal hematopoietic cells in bone marrow, no detectable blasts, ≥ 50% decrease of blasts in BMA & total bone marrow blasts of 5-25%. No evidence of extramedullary leukemia. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25% |
| Phase 2 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.4 years) | An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE for Phase 2 was defined as an AE observed after the date of first dose until 30 days after the last dose. TEAE included both serious and non-serious AEs. |
| Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period | IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years) | Percentage of participants with CRc reported. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recovery (CRi). CRp: met all CR criteria, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP. |
| Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1 | Tmax was derived from the PK samples collected. |
| Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1 | AUC24 was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated. |
| Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1 | AUClast was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated. |
| Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Pre-dose on Cycle 1 Day 8, 11, and 17 Consolidation period: Pre-dose on Cycle 1 Day 6 and 15 | Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated. |
Countries
Japan, South Korea, Taiwan
Participant flow
Recruitment details
Participants with newly diagnosed acute myeloid leukemia (AML) and participants newly diagnosed FMS-like tyrosine kinase-3, FMS-related tyrosine kinase 3 (FLT3)-mutated AML; were enrolled in Phase 1 and Phase 2, respectively.
Pre-assignment details
Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Dose Evaluation (DEv) Induction period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Duration of infusion was determined based on site clinical practice and the local package insert.
Consolidation period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert.
Maintenance period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days). | 3 |
| Phase 1: Dose Expansion (DEx) Induction period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 4 to 17 in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2 (1 cycle= 42 days). Duration of infusion was determined based on site clinical practice and the local package insert.
Consolidation period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 14 in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3 (1 cycle= 28 days). Duration of infusion was determined based on site clinical practice and the local package insert.
Maintenance period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days). | 10 |
| Phase 2: FLT3-mutated AML Induction period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 8 until blood recovery in combination with chemotherapy (idarubicin: 12 mg/m\^2/day on days 1 to 3, cytarabine: 100 mg/m\^2/day on days 1 to 7) via IV infusion; in the induction period in C1 and 2. Each cycle was allowed to be extended until blood recovery was observed. Duration of infusion was determined based on site clinical practice and the local package insert.
Consolidation period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 until blood recovery in combination with chemotherapy (cytarabine: 1500 mg/m\^2, twice daily on days 1, 3, and 5) via IV infusion; in the consolidation period in C1 to 3. Each cycle was allowed to be extended until blood recovery was observed. Duration of infusion was determined based on site clinical practice and the local package insert.
Maintenance period:
Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day from days 1 to 28 in the maintenance period in C1 to 26 or a discontinuation criterion is met (1 cycle= 28 days). | 84 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1(DEv):CP (3 Cycles;28 Days/Cycle) | Miscellaneous | 1 | 0 | 0 |
| Phase 1(DEv):IP (2 Cycles;42 Days/Cycle) | Miscellaneous | 1 | 0 | 0 |
| Phase 1(DEv):MP(26 Cycles;28 Days/Cycle) | Miscellaneous | 1 | 0 | 0 |
| Phase 1(DEx):IP (2 Cycles;42 Days/Cycle) | Adverse Event | 0 | 1 | 0 |
| Phase 1(DEx):IP (2 Cycles;42 Days/Cycle) | Disease Relapse | 0 | 1 | 0 |
| Phase 1(DEx):IP (2 Cycles;42 Days/Cycle) | Miscellaneous | 0 | 4 | 0 |
| Phase 1(DEx):IP (2 Cycles;42 Days/Cycle) | There is no CR, CRp, or CRi after 2 Cycles of Therapy | 0 | 1 | 0 |
| Phase 1(DEx):MP(26 Cycles;28 Days/Cycle) | Micellaneous | 0 | 3 | 0 |
| Phase 2:CP(4 Cycles;up to 28 Days/Cycle) | Disease Relapse | 0 | 0 | 4 |
| Phase 2:CP(4 Cycles;up to 28 Days/Cycle) | Miscellaneous | 0 | 0 | 7 |
| Phase 2:CP(4 Cycles;up to 28 Days/Cycle) | Physician Decision | 0 | 0 | 4 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Adverse Event | 0 | 0 | 2 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Death | 0 | 0 | 3 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Disease Relapse | 0 | 0 | 2 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Lack of Efficacy | 0 | 0 | 3 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Miscellaneous | 0 | 0 | 2 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Physician Decision | 0 | 0 | 6 |
| Phase 2:IP(2 Cycles;up to 56 Days/Cycle) | Withdrawal by Subject | 0 | 0 | 4 |
| Phase 2:MP(26 Cycles; 28 Days/Cycle) | Adverse Event | 0 | 0 | 3 |
| Phase 2:MP(26 Cycles; 28 Days/Cycle) | Death | 0 | 0 | 1 |
| Phase 2:MP(26 Cycles; 28 Days/Cycle) | Disease relapse | 0 | 0 | 11 |
| Phase 2:MP(26 Cycles; 28 Days/Cycle) | Miscellaneous | 0 | 0 | 2 |
| Phase 2:MP(26 Cycles; 28 Days/Cycle) | Physician Decision | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Phase 1: Dose Evaluation (DEv) | Phase 1: Dose Expansion (DEx) | Phase 2: FLT3-mutated AML | Total |
|---|---|---|---|---|
| Age, Continuous | 48.3 Years STANDARD_DEVIATION 14 | 49.9 Years STANDARD_DEVIATION 15 | 51 Years STANDARD_DEVIATION 14.4 | 50.8 Years STANDARD_DEVIATION 14.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 84 Participants | 97 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 10 Participants | 84 Participants | 97 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 43 Participants | 48 Participants |
| Sex: Female, Male Male | 1 Participants | 7 Participants | 41 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 10 | 25 / 84 |
| other Total, other adverse events | 3 / 3 | 10 / 10 | 84 / 84 |
| serious Total, serious adverse events | 2 / 3 | 1 / 10 | 45 / 84 |
Outcome results
Primary
Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib
The MTD was defined as the highest dose of gilteritinib at which the posterior mean of the DLT incidence during Cycle 1 of induction therapy was estimated to be closest to 33%.
Time frame: Day 1 up to the end of Induction period cycle 1 (up to 42 days)
Population: Dose-Determining Analysis Set (DDAS) Phase 1 part: Participants who received more than 80% of the intended dose of gilteritinib and safety was adequately assessed during DLT assessment period specified in each part were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Maximum Tolerated Dose (MTD) of Gilteritinib | NA miligram (mg) |
Primary
Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib
DLTs were defined as: Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: * Anorexia or fatigue * Grade 3 nausea and/or vomiting if participant did not require tube feeding or total parenteral nutrition, or diarrhea if the events did not require or prolong hospitalization that could be managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset. * Grade 3 mucositis that resolved to Grade ≤ 2 within 7 days of onset, fever with neutropenia, with or without infection, infection * Grade 4 peripheral neutrophil count \< 500/cubic millimeters (mm\^3) * Platelet count \< 20,000/mm\^3 due to bone marrow hypoplasia * Grade ≥ 3 platelet count \< 50,000/mm\^3 accompanying bleeding * Grade 4 platelet count \< 25,000/mm\^3 requiring platelet transfusion DLT was assessed until cycle 1 of dose evaluation induction period and until cycle 1 of dose expansion consolidation period.
Time frame: Day 1 up to the end of Consolidation Cycle 1 (approximately up to 4 months)
Population: Participants in the DDAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib | 0 Participants |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Number of Participants With Dose Limiting Toxicities (DLTs) of Gilteritinib | 1 Participants |
Primary
Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE included both serious and non-serious AEs. TEAE for Phase 1 was defined as an AE observed after the date of first dose until 30 days after the last dose.
Time frame: From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.1 years)
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 3 Participants |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 10 Participants |
Primary
Phase 1 Part: Recommended Expansion Dose (RED) of Gilteritinib
RED was the recommended dose used in Phase 2 of the study that was decided by the sponsor's responsible person by comprehensively assessing the data obtained from the study.
Time frame: Day 1 up to the end of Induction period cycle 1 (up to 42 days)
Population: Participants in the DDAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Recommended Expansion Dose (RED) of Gilteritinib | 120 mg |
Primary
Phase 2 Part: Complete Remission (CR) Rate: Induction Period
Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm3 and platelet count of ≥ 100,000/mm3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%.
Time frame: From the date of first dose up to the start of Consolidation (approximately up to 4 months)
Population: Participants in the Full Analysis Set (FAS) Phase 2 part: Participants who received at least 1 dose of study drug and had at least one post-baseline bone marrow assessment were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Complete Remission (CR) Rate: Induction Period | 50 Percentage of participants |
Secondary
Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
AUC24 was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Time frame: Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 3880 ng*hr/mL | Standard Deviation 2530 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 2110 ng*hr/mL | — |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 2210 ng*hr/mL | Standard Deviation 567 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Area Under Plasma Concentration-time Curve From Time 0 to 24 (AUC24) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 1160 ng*hr/mL | Standard Deviation 204 |
Secondary
Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
AUClast was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Time frame: Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 3830 ng*hr/mL | Standard Deviation 2520 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 2090 ng*hr/mL | — |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 2190 ng*hr/mL | Standard Deviation 552 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Area Under The Concentration-Time Curve From The Time Zero to The Last Measurable Concentration (AUClast) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 1150 ng*hr/mL | Standard Deviation 202 |
Secondary
Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
Cmax was derived from the PK samples collected. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Time frame: Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1
Population: Pharmacokinetics Analysis Set (PKAS): Participants who received the study drug, from whom samples for drug concentration measurement were collected for at least 1 time-point after the study drug administration, and from whom drug concentration measurement was obtained were included. PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction Period | 246 nanograms per milliliter (ng/mL) | Standard Deviation 154 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 133 nanograms per milliliter (ng/mL) | — |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction Period | 132 nanograms per milliliter (ng/mL) | Standard Deviation 27.5 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Maximum Concentration (Cmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 73.5 nanograms per milliliter (ng/mL) | Standard Deviation 17.5 |
Secondary
Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Time frame: Induction period: Pre-dose on Cycle 1 Day 8, 11, and 17 Consolidation period: Pre-dose on Cycle 1 Day 6 and 15
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 11 | 283 ng/mL | Standard Deviation 183 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period: Cycle 1 day 6 | 194 ng/mL | — |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 17 | 393 ng/mL | Standard Deviation 252 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period: Cycle 1 day 15 | 285 ng/mL | — |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 8 | 245 ng/mL | Standard Deviation 144 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period: Cycle 1 day 15 | 171 ng/mL | Standard Deviation 154 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 8 | 245 ng/mL | Standard Deviation 77.7 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 11 | 417 ng/mL | Standard Deviation 203 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period: Cycle 1 day 17 | 455 ng/mL | Standard Deviation 143 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration (Ctrough) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period: Cycle 1 day 6 | 159 ng/mL | Standard Deviation 12.1 |
Secondary
Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period
Ctrough is the plasma concentration prior to drug administration. It was planned that standard deviation(SD) would only be calculated if there are more than 3 participants analyzed otherwise, SD was not calculated.
Time frame: Induction period: Predose on Cycle 1 Day 1, 3, and 8 Consolidation period: Predose on Cycle 1 Day 2 and 6
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 3 | 34.9 ng/mL | Standard Deviation 14.5 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Consolidation period: Cycle 1 Day 2 | 4.87 ng/mL | — |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 8 | 58.8 ng/mL | Standard Deviation 8.67 |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Consolidation period: Cycle 1 Day 6 | 7.09 ng/mL | — |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 1 | 0 ng/mL | — |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Consolidation period: Cycle 1 Day 6 | 11.8 ng/mL | Standard Deviation 1.91 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 1 | 0 ng/mL | — |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 3 | 210 ng/mL | Standard Deviation 417 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Induction period: Cycle 1 Day 8 | 110 ng/mL | Standard Deviation 107 |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Plasma Trough Concentration of Cytarabine Concomitant With Gilteritinib With Induction and Consolidation Period | Consolidation period: Cycle 1 Day 2 | 9.39 ng/mL | Standard Deviation 2.19 |
Secondary
Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
Tmax was derived from the PK samples collected.
Time frame: Induction period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 4 Consolidation period: Pre-dose, 1, 2, 4, 6, 10, and 24 hours post-dose on Cycle 1 Day 1
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 3.93 hours |
| Phase 1: Dose Evaluation (DEv) | Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 2.94 hours |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction period | 5.77 hours |
| Phase 1: Dose Expansion (DEx) | Phase 1 Part: Time to Attain Cmax (Tmax) of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation period | 4.32 hours |
Secondary
Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period
Percentage of participants with CRc reported. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recovery (CRi). CRp: met all CR criteria, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP.
Time frame: IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years)
Population: The analysis population consisted of FAS participants, regardless of whether they proceeded to induction, consolidation or maintenance. CR rate after: induction included participants from start of treatment through induction; consolidation included participants from induction through consolidation and maintenance included participants from induction through maintenance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period | After Induction Period | 86.6 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period | After Consolidation Period | 87.8 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Composite CR (CRc) Rate After Each Treatment Therapy Period | After Maintenance Period | 87.8 Percentage of participants |
Secondary
Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period
Percentage of participants with CR/CRh was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP.
Time frame: IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years)
Population: The analysis population consisted of FAS participants, regardless of whether they proceeded to induction, consolidation or maintenance. CR rate after: induction included participants from start of treatment through induction; consolidation included participants from induction through consolidation and maintenance included participants from induction through maintenance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period | After Induction Period | 67.1 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period | After Consolidation Period | 73.2 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR/CRh Rate After Each Treatment Therapy Period | After Maintenance Period | 73.2 Percentage of participants |
Secondary
Phase 2 Part: CR Rate After Consolidation and Maintenance Period
Percentage of participants with CR was reported. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the consolidation period refers to the best response from the start of treatment in the induction period until the end of the consolidation period and for the maintenance period refers to the best response from the start of treatment in the induction period until the end of the maintenance period.
Time frame: CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years)
Population: The analysis population consisted of FAS participants, regardless of whether they proceeded to consolidation or maintenance. CR rate after consolidation included participants from induction through consolidation and CR rate after maintenance included participants from induction through maintenance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR Rate After Consolidation and Maintenance Period | After consolidation period | 63.4 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR Rate After Consolidation and Maintenance Period | After maintenance period | 63.4 Percentage of participants |
Secondary
Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period
CR% without MRD reported. CR rate without MRD after each treatment therapy was defined similarly as CR rate after each treatment therapy. Responders achieve that the best response is CR and MRD status was negative. CR was defined as a morphologically leukemia-free state, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP.
Time frame: IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years)
Population: The analysis population consisted of FAS participants, regardless of whether they proceeded to induction, consolidation or maintenance. CR rate after: induction included participants from start of treatment through induction; consolidation included participants from induction through consolidation and maintenance included participants from induction through maintenance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period | After Induction Period | 18.3 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period | After Consolidation Period | 35.4 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR Rate Without Minimal Residual Disease (MRD) After Each Treatment Therapy Period | After Maintenance Period | 35.4 Percentage of participants |
Secondary
Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period
Percentage of participants with CRh was reported. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Derived response assessment after the IP refers to the best response from the start of treatment in the IP until the end of the IP, after CP refers to the best response from the start of treatment in the IP until the end of the CP and for the MP refers to the best response from the start of treatment in the IP until the end of the MP.
Time frame: IP: From date of first dose up to end of period (approximately 1.4 years), CP: From date of first dose up to end of period (approximately 1.8 years), MP: From date of first dose up to the end of period (approximately 3.8 years)
Population: The analysis population consisted of FAS participants, regardless of whether they proceeded to induction, consolidation or maintenance. CR rate after: induction included participants from start of treatment through induction; consolidation included participants from induction through consolidation and maintenance included participants from induction through maintenance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period | After Induction Period | 17.1 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period | After Consolidation Period | 9.8 Percentage of participants |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: CR With Partial Hematological Recovery (CRh) Rate After Each Treatment Therapy Period | After Maintenance Period | 9.8 Percentage of participants |
Secondary
Phase 2 Part: Duration of CR
Duration of CR was defined as the time from the date of achieving first CR until the date of first documented relapse for participants who achieved CR. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Time frame: From the date of achieving CR up to the date of documented relapse (maximum duration: approximately 2.6 years)
Population: FAS with available data analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Duration of CR | NA Months |
Secondary
Phase 2 Part: Duration of CRc
Duration of CRc is defined as the time from the date of achieving first CRc until the date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Time frame: From the date of achieving CRc up to the date of documented relapse (maximum duration: approximately 2.7 years)
Population: FAS with available data analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Duration of CRc | NA Months |
Secondary
Phase 2 Part: Duration of CR/CRh
Duration of CR/CRh is defined as the time from the date of achieving first CR/CRh until the date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis. CR was defined as a morphologically leukemia-free state at the post-baseline visit, having a neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods and no evidence of extramedullary leukemia. The blast counts in peripheral blood was ≤ 2%. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Time frame: From the date of achieving CR/CRh up to the date of documented relapse (maximum duration: approximately 2.6 years)
Population: FAS with available data analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Duration of CR/CRh | NA Months |
Secondary
Phase 2 Part: Duration of CRh
Duration of CRh was defined as the time from date of achieving first CRh until date of first documented relapse for participants who achieved CRh. KM estimate was used for analysis. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery neutrophil count≥ 500/mm\^3 and platelet count ≥ 50,000/mm\^3, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%.
Time frame: From the date of achieving CRh up to the date of documented relapse (maximum duration: approximately 2.6 years)
Population: FAS with available data analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Duration of CRh | NA Months |
Secondary
Phase 2 Part: Duration of Response (DoR)
DoR: from first day of achieving CRc (CR+ CRp,+CRi)/partial remission (PR) to first day of relapse. KM estimate was used for analysis. CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 & platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Peripheral blood blast counts was ≤ 2%. CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). PR: condition with regeneration of normal hematopoietic cells in bone marrow, no detectable blasts, ≥ 50% decrease of blasts in BMA & total bone marrow blasts of 5-25%. No evidence of extramedullary leukemia. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in BMA/reappearance of numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%
Time frame: From the date of achieving CR, CRp, CRi/PR up to the date of documented relapse (maximum duration: approximately 2.7 years)
Population: FAS with available data analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Duration of Response (DoR) | NA Months |
Secondary
Phase 2 Part: Event Free Survival (EFS)
Event-free survival (EFS): time from date of first dose of study regimen until date of documented relapse, treatment failure or death from any cause, whichever occurred first. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. Treatment failure: participants who failed to achieve composite complete remission (CRc) or who discontinued treatment due to lack of efficacy without previous response. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: defined in outcome measure #5.
Time frame: From the date of first dose up to the date of documented relapse, treatment failure or death from any cause (maximum duration: approximately 4.4 years)
Population: TTE-FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Event Free Survival (EFS) | 25.0 Months |
Secondary
Phase 2 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE could therefore be any unfavorable & unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. TEAE for Phase 2 was defined as an AE observed after the date of first dose until 30 days after the last dose. TEAE included both serious and non-serious AEs.
Time frame: From the date of first dose up to 30 days after the last dose ( maximum duration up to approximately 4.4 years)
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 84 Participants |
Secondary
Phase 2 Part: Overall Survival (OS)
Overall survival (OS) was defined as the time from the date of first dose of day 1 to the date of death due to any cause. Participants still alive or lost to follow up was censored at the time they were last known to be alive. Kaplan-Meier (KM) estimate was used for analysis.
Time frame: From the date of first dose up to the date of death (maximum duration: approximately 4.4 years)
Population: Time-to-Event-FAS (TTE-FAS): All participants who received at least 1 dose of gilteritinib with or without postbaseline bone marrow assessments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Overall Survival (OS) | 48.2 Months |
Secondary
Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy
Ctrough is the plasma concentration prior to drug administration.
Time frame: Induction period : Predose on Cycle 1 Day 15 and 21 Consolidation period: Predose on Cycle 1 Day 8 and 15
Population: PKAS with available data analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction Period: Cycle 1 Day 15 | 522 ng/mL | Standard Deviation 331 |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Induction Period: Cycle 1 Day 21 | 647 ng/mL | Standard Deviation 518 |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation Period: Cycle 1 Day 8 | 244 ng/mL | Standard Deviation 152 |
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Plasma Trough Concentration of Gilteritinib Concomitant With Induction and Consolidation Chemotherapy | Consolidation Period: Cycle 1 Day 15 | 375 ng/mL | Standard Deviation 249 |
Secondary
Phase 2 Part: Relapse Free Survival (RFS)
Relapse-free survival (RFS): time from date of achievement of first CRc until relapse or death from any cause. KM estimate was used for analysis. Relapse: reappearance of leukemic blasts in peripheral blood (\>2%)/≥ 5% blasts in bone marrow aspirate (BMA)/reappearance of significant numbers of peripheral blasts and an increase in percentage of blasts in BMA to \> 25%. CRc: rate of all complete & incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). CRp: met all CR criteria at post-baseline visit, except unrecovered platelet count (\< 100,000/mm\^3). CRi: met all CR criteria at post-baseline visit, except unrecovered neutrophil count (\< 1,000/mm\^3). CR: morphologically leukemia-free state at post-baseline visit, having neutrophil count of ≥ 1,000/mm\^3 and platelet count of ≥ 100,000/mm\^3, bone marrow blasts \< 5%. No evidence of Auer rods & extramedullary leukemia. Blast counts in peripheral blood was ≤ 2%.
Time frame: From the date of achievement of first CRc up to the date of documented relapse or death from any cause (maximum duration: approximately 3.9 years)
Population: FAS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Dose Evaluation (DEv) | Phase 2 Part: Relapse Free Survival (RFS) | 27.8 Months |