AML With FLT3 Mutation
Conditions
Keywords
gilteritinib, Acute Myeloid Leukemia (AML), ASP2215
Brief summary
The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated AML who were refractory to or had relapse after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study evaluated safety as well as determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.
Detailed description
Participants considered an adult according to local regulations at the time of signing informed consent were randomized in a 1:1 ratio and received ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator preselected a salvage chemotherapy regimen for each participant; options included low-dose cytarabine (LoDAC), mitoxantrone, etoposide and intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization was stratified by response to first-line therapy and preselected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. Among the participants, approximately 20 Chinese participants who were randomized into the ASP2215 arm were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were requested to be hospitalized from the date of randomization (Day 1) to at least the completion of all the assessments planned on Day 2. All participants in the PK cohort underwent blood sampling for PK measurement of ASP2215. Participants in PK cohort were administered the study drug in the same manner and underwent the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.
Interventions
DRUGGilteritinib
Tablet administered orally once daily.
DRUGCytarabine
Once/twice daily Intravenously (IV)/subcutaneously (SC).
DRUGMitoxantrone
Once daily IV injection.
DRUGEtoposide
Once daily IV injection.
DRUGG-CSF
Once daily IV/SC injection.
DRUGFludarabine
Once daily IV injection.
Sponsors
Astellas Pharma 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
* Participant has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization (WHO) classification as determined by pathology review at the treating institution. * Participant is refractory to or relapsed after first-line AML therapy (with or without HSCT) * Refractory to first-line AML therapy is defined as: a. Participant did not achieve CR/CRi/CRp under initial therapy. A participant eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A participant not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this participant. * Untreated first hematologic relapse is defined as: 1. Participant must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse. * Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A participant with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Participants can be enrolled from a local test result if the participants have any of the following FLT3 mutations: FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD)/D835 or FLT3-TKD/I836. * Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Participant is eligible for preselected salvage chemotherapy. * Participant must meet the following criteria as indicated on the clinical laboratory tests: * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) * Serum total bilirubin (TBL) ≤ 1.5 x ULN * Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of \> 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. * Participant is suitable for oral administration of study drug. * Participant agrees not to participate in another interventional study while on treatment. Inclusion Criteria for COE: Participant is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the participant is evaluated for eligibility to participate in the COE portion of the study: * Participant has received study treatment of either LoDAC, MEC or FLAG and has no response or progressive disease. * Participant have not received other antileukemic therapy after EOT (hydroxyurea is allowed for the control of peripheral leukemic blasts in participants with leukocytosis). * Participant agrees not to participate in another interventional study while on treatment.
Exclusion criteria
* Participant was diagnosed as acute promyelocytic leukemia. * Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis). * Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS). * Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease. * Participant has clinically active central nervous system leukemia.. * Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy. * Participant has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation and/or maintenance). * Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation. * Participant has had major surgery within 4 weeks prior to the first study dose. * Participant has radiation therapy within 4 weeks prior to the first study dose. * Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or participant with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%. * Participant with mean of triplicate Fridericia-corrected QT interval (QTcF) \> 450 ms at Screening based on central reading. * Participant with Long QT Syndrome at Screening. * Participant with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal \[LLN\]). * Participant requires treatment with concomitant drugs that are strong inducers of CYP3A. * Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the participant. * Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the participant. * Participant has an active uncontrolled infection. * Participant is known to have human immunodeficiency virus infection. * Participant has active hepatitis B or C or other active hepatic disorder. * Participant has any condition which makes the participant unsuitable for study participation. * Participant has active clinically significant (graft-versus-host disease) GVHD or is on treatment with systemic corticosteroids for GVHD. * Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the date of randomization up to the date of death (up to approximatley 74 months) | OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were still alive or lost to follow up were censored at the time they were last known to be alive. Kaplan-Meier (KM) estimates was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | From the date of randomization up to the date of documented relapse, treatment failure or death from any cause, off-treatment relapse and start of new AML therapy (up to approximately 74 months) | EFS: time from the date of randomization until the date of documented relapse, treatment failure, death, reported off treatment relapse or new AML therapy start whichever occued first, including the long-term follow-up data. KM estimate was used for analysis. Relapse was defined as documentation of any of following events: * Bone marrow (BM) blasts ≥ 5% (not attributable to regenerating BM) * Reappearance or new appearance of extramedullary leukemia * Reappearance of significant numbers of peripheral blasts Treatment failure: Treatment failure was defined as participant who ends treatment without having a previous response of CR, CR with incomplete platelet recovery (CRp) and CR with incomplete hematological recover (CRi). |
| Complete Remission (CR) Rate | From the date of randomization up to approximately 74 months | Percentage of participants with CR were reported. CR: morphologically leukemia-free state, with absolute neutrophil count (ANC) \> 1x10\^9 per liter (1x10\^9/L), platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were red blood cell (RBC) and platelet transfusion independent and no evidence of extramedullary leukemia or Auer rods was necessary. |
| Duration of CR | From date of achieving CR until date of confirmed relapse (maximum duration was 53.4 months ) | Duration of CR: time from the date of achieving first CR until date of first documented relapse for participants who achieved CR. KM estimate was used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. Relapse was defined as documentation of any of following events: * BM blasts ≥ 5% (not attributable to regenerating BM) * Reappearance or new appearance of extramedullary leukemia * Reappearance of significant numbers of peripheral blasts |
| Duration of Composite Complete Remission (CRc) | From date of achieving CRc until date of confirmed relapse (maximum duration was 60 months) | Duration of CRc: time from date of achieving first CRc until date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis. CRc: rate of all complete \& incomplete remissions \[CR + CRp + CRi\]. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts. |
| Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh) | From date of achieving CR/CRh until date of confirmed relapse (maximum duration was 58.1 months) | Duration of CR/CRh: time from date of achieving first CR/CRh until date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts. |
| Duration Of Response (DOR) | From date of achieving CRc/PR until date of confirmed relapse (maximum duration was 52.1 months) | DOR: time from date of first CRc (CR+CRp+CRi)/PR until date of first documented relapse for participants who achieved CRc or PR. KM estimate used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts and increase in the percentage of blasts in the BM aspirate to \> 25%. |
| CR/CRh Rate | From the date of randomization up to approximately 74 months | Percentage of participants with CR/CRh was reported. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%. |
| Best Response Rate | From the date of randomization up to approximately 74 months | Defined as percentage of participants with CR, CRp, CRi, PR, no response (NR) \& not estimable (NE). CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L \& normal marrow differential with \< 5% blasts. They were RBC \& platelet transfusion independent \& no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\<100x10\^9/L). CRi: met all CR criteria, except incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with/without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%. \<=5% BM blasts if Auer rods are present, no evidence of extramedullary leukemia. Not Estimable (NE): No BM assessed/no myeloblast value, no blast value from peripheral blood or ≤2%, \& no extramedullary leukemia. No Response (NR): Response not categorized as CR, CRp, CRi, PR or NE. |
| Leukemia-Fee Survival (LFS) | From first day of achieving first CRc to the first day of confirmed relapse/death (maximum duration was 60.0 months) | LFS: time from the date of first CRc (CR+CRp+CRi) until the date of documented relapse or death for participants who achieved CRc. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts. |
| Composite Complete Remission (CRc) | From the date of randomization up to approximately 74 months | Percentage of participants with CRc (CR+CRp+CRi) was reported. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. |
| Time to CRc | From randomization until date of first CRc (up to approximately 74 months) | Time to CRc (TTCRc) was defined as the time from the date of randomization until the date of first CRc. CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. |
| Time to CR | From randomization until date of first CR (up to approximately 74 months) | Time to CR (TTCR) was defined as the time from the date of randomization until the date of first CR. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. |
| Time to Response | From randomization until date of first CRc or PR (up to approximately 74 months) | Time to Response (TTR) was defined as the time from the date of randomization until the date of either first response (CRc or PR). CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate \& total BM blasts of 5-25%. |
| Time to CR/CRh | From randomization until date of first CR/CRh (up to approximately 74 months) | Time to CR/CRh (TTCRCRh) was defined as the time from the date of randomization until the date of first CR/CRh. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%. |
| Percentage of Participants With Transfusion Conversion and Transfusion Maintenance | Baseline up to approximately 74 months | Transfusion conversion rate: Percentage of transfusion dependent participants at baseline period but became transfusion independent at post-baseline period divided by total participants who were transfusion dependent at baseline period. Transfusion maintenance rate: Percentage of transfusion independent participants at baseline period and still maintained transfusion independent at post-baseline period divided by total participants who were transfusion independent at baseline period. Baseline transfusion status: Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to first dose to 28 days after first dose; otherwise classified as transfusion dependent. Post baseline transfusion status: Participants on treatment ≥ 84 days were classified as transfusion independent, if consecutive 56 days without any RBC or platelet transfusion; otherwise classified as transfusion dependent |
| Percentage of Participants With Transplantation Rate | Baseline up to approximately 74 months | Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period. |
| Change From Baseline in Brief Fatigue Inventory (BFI) | Baseline, End of treatment (63 months) | The BFI is a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions ask participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions ask participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI, ranging between 0 to 10; a higher BFI fatigue score indicates worse outcome. The global BFI scores were calculated only if at least 5 of the 9 items are answered. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From the date of first dose up to approximately 74 months | 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 was defined as an adverse event observed after starting administration of the study drug. |
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Baseline, end of treatment visit (63 months) | The ECOG Scale was used to assess performance status. Number of participants with each grade was reported. Grade Description: 0: Fully active, able to carry on all pre-disease performance without restriction. 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead. |
| Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24) | Cycle 1 Day 1(C1D1): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, Cycle 1 Day 15(C1D15): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose | AUC24 was derived from the PK samples collected. |
| PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax) | C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose | Cmax was derived from the PK samples collected. |
| PK of Gilteritinib: Observed Trough Concentration (Ctrough) | Predose on C1D15 | Ctrough was derived from the PK samples collected. |
| PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax) | C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose | tmax was derived from the PK samples collected. |
| Ctrough Concentration of Gilteritinib | Predose C1D8, C1D15, Day 1 of each cycle from C2 to C65, C67D1,C68D1,C69D1,C70D1 | Concentrations below the lower limit of quantification (0.5 ng/mL) were set to zero. |
Countries
China, Malaysia, Russia, Singapore, Thailand
Contacts
STUDY_DIRECTORMedical Director
Astellas Pharma Inc
Participant flow
Recruitment details
Participants with FMS-like tyrosine kinase 3 (FLT3) mutations with relapsed or refractory Acute Myeloid Leukemia (AML) after first-line therapy were enrolled for this study. 21 participants from six china sites were included in Giltertinib PK cohort.
Pre-assignment details
Randomization was stratified by response to first-line therapy and preselected salvage chemotherapy. Results were reported up to primary analysis data cut-off of 25 December 2023 (approximately 74 months).
Participants by arm
| Arm | Count |
|---|---|
| Gilteritinib Participants received 120 mg gilteritinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles until treatment discontinuation criteria were met. Participants who met the treatment discontinuation criteria, entered the long-term follow-up period. Participants remained in the long-term follow-up period for up to 3 years from the participant's end of treatment visit or until discontinuation from the study. | 137 |
| Salvage Chemotherapy Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines.
Salvage chemotherapy included:
LoDAC: 20 mg cytarabine administered twice daily by SC/IV injection for 10 days.
MEC: mitoxantrone 6 mg/m\^2 per day administered by IV for 5 days (days 1 through 5), etoposide 100 mg/m\^2 per day administered by IV for 5 days (days 1 through 5), cytarabine 1000 mg/m\^2 per day administered by IV for 5 days (days 1 through 5).
FLAG: G-CSF 300 μg/m\^2 per day administered by SC/IV for 5 days (days 1 through 5), fludarabine 30 mg/m\^2 per day administered by IV for 5 days (days 2 through 6), cytarabine 2000 mg/m\^2 per day administered by IV for 5 days (days 2 through 6). Participants who met treatment discontinuation criteria, entered long-term follow-up and remained in the period for up to 3 years from the participant's end of treatment visit/until discontinuation from study.
Based on the outcome of interim analysis, at investigators discretion, participants in the treatment period had the option to enter COE period to receive 120 mg gilteritinib, orally, once a day in continuous 28-day cycles until treatment discontinuation criteria was met. | 139 |
| Total | 276 |
Baseline characteristics
| Characteristic | Salvage Chemotherapy | Total | Gilteritinib |
|---|---|---|---|
| Age, Continuous | 46.2 Years STANDARD_DEVIATION 15.1 | 46.6 Years STANDARD_DEVIATION 15.7 | 46.9 Years STANDARD_DEVIATION 16.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 139 Participants | 275 Participants | 136 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Preselected Salvage Chemotherapy High intensity chemotherapy | 112 Participants | 222 Participants | 110 Participants |
| Preselected Salvage Chemotherapy Low intensity chemotherapy | 27 Participants | 54 Participants | 27 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 120 Participants | 243 Participants | 123 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 33 Participants | 14 Participants |
| Region of Enrollment China | 92 participants | 182 participants | 90 participants |
| Region of Enrollment Malaysia | 14 participants | 29 participants | 15 participants |
| Region of Enrollment Russia | 19 participants | 33 participants | 14 participants |
| Region of Enrollment Singapore | 4 participants | 8 participants | 4 participants |
| Region of Enrollment Thailand | 10 participants | 24 participants | 14 participants |
| Response to First-Line Therapy Primary refractory without HSCT | 81 Participants | 161 Participants | 80 Participants |
| Response to First-Line Therapy Relapse after 6 months after allogeneic HSCT | 2 Participants | 4 Participants | 2 Participants |
| Response to First-Line Therapy Relapse after 6 months after CRc and no HSCT | 23 Participants | 46 Participants | 23 Participants |
| Response to First-Line Therapy Relapse within 6 months after allogeneic HSCT | 4 Participants | 5 Participants | 1 Participants |
| Response to First-Line Therapy Relapse within 6 months after CRc and no HSCT | 29 Participants | 60 Participants | 31 Participants |
| Sex: Female, Male Female | 70 Participants | 146 Participants | 76 Participants |
| Sex: Female, Male Male | 69 Participants | 130 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 97 / 137 | 85 / 139 |
| other Total, other adverse events | 133 / 134 | 113 / 119 |
| serious Total, serious adverse events | 102 / 134 | 71 / 119 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from the date of randomization to the date of death due to any cause. Participants who were still alive or lost to follow up were censored at the time they were last known to be alive. Kaplan-Meier (KM) estimates was used for analysis.
Time frame: From the date of randomization up to the date of death (up to approximatley 74 months)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Overall Survival (OS) | 10.3 months |
| Salvage Chemotherapy | Overall Survival (OS) | 5.4 months |
p-value: 0.0015295% CI: [0.451, 0.832]Log Rank
Secondary
Best Response Rate
Defined as percentage of participants with CR, CRp, CRi, PR, no response (NR) & not estimable (NE). CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L & normal marrow differential with \< 5% blasts. They were RBC & platelet transfusion independent & no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\<100x10\^9/L). CRi: met all CR criteria, except incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with/without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate & total BM blasts of 5-25%. \<=5% BM blasts if Auer rods are present, no evidence of extramedullary leukemia. Not Estimable (NE): No BM assessed/no myeloblast value, no blast value from peripheral blood or ≤2%, & no extramedullary leukemia. No Response (NR): Response not categorized as CR, CRp, CRi, PR or NE.
Time frame: From the date of randomization up to approximately 74 months
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib | Best Response Rate | NR | 27.7 Percentage of participants |
| Gilteritinib | Best Response Rate | PR | 14.6 Percentage of participants |
| Gilteritinib | Best Response Rate | CR | 20.4 Percentage of participants |
| Gilteritinib | Best Response Rate | CRi | 19.7 Percentage of participants |
| Gilteritinib | Best Response Rate | NE | 4.4 Percentage of participants |
| Gilteritinib | Best Response Rate | CRp | 13.1 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | NE | 38.1 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | CR | 11.5 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | CRp | 0.7 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | CRi | 10.1 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | PR | 5.0 Percentage of participants |
| Salvage Chemotherapy | Best Response Rate | NR | 34.5 Percentage of participants |
Secondary
Change From Baseline in Brief Fatigue Inventory (BFI)
The BFI is a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions ask participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions ask participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI, ranging between 0 to 10; a higher BFI fatigue score indicates worse outcome. The global BFI scores were calculated only if at least 5 of the 9 items are answered.
Time frame: Baseline, End of treatment (63 months)
Population: ITT population with data available at specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gilteritinib | Change From Baseline in Brief Fatigue Inventory (BFI) | 1.42 Scores on scale | Standard Deviation 2.99 |
| Salvage Chemotherapy | Change From Baseline in Brief Fatigue Inventory (BFI) | 0.75 Scores on scale | Standard Deviation 2.92 |
p-value: 0.14841ANCOVA
Secondary
Complete Remission (CR) Rate
Percentage of participants with CR were reported. CR: morphologically leukemia-free state, with absolute neutrophil count (ANC) \> 1x10\^9 per liter (1x10\^9/L), platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were red blood cell (RBC) and platelet transfusion independent and no evidence of extramedullary leukemia or Auer rods was necessary.
Time frame: From the date of randomization up to approximately 74 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib | Complete Remission (CR) Rate | 20.4 Percentage of participants |
| Salvage Chemotherapy | Complete Remission (CR) Rate | 11.5 Percentage of participants |
p-value: 0.0425695% CI: [0.3, 17.5]Cochran-Mantel-Haenszel
Secondary
Composite Complete Remission (CRc)
Percentage of participants with CRc (CR+CRp+CRi) was reported. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery.
Time frame: From the date of randomization up to approximately 74 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib | Composite Complete Remission (CRc) | 53.3 Percentage of participants |
| Salvage Chemotherapy | Composite Complete Remission (CRc) | 22.3 Percentage of participants |
p-value: <0.0000195% CI: [20.2, 42.3]Cochran-Mantel-Haenszel
Secondary
CR/CRh Rate
Percentage of participants with CR/CRh was reported. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and could be classified as CR. The blast counts in peripheral blood was ≤ 2%.
Time frame: From the date of randomization up to approximately 74 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib | CR/CRh Rate | 32.1 Percentage of participants |
| Salvage Chemotherapy | CR/CRh Rate | 14.4 Percentage of participants |
p-value: 0.0004995% CI: [7.9, 27.5]Cochran-Mantel-Haenszel
Secondary
Ctrough Concentration of Gilteritinib
Concentrations below the lower limit of quantification (0.5 ng/mL) were set to zero.
Time frame: Predose C1D8, C1D15, Day 1 of each cycle from C2 to C65, C67D1,C68D1,C69D1,C70D1
Population: PKAS with available data at timepoint were analyzed. This endpoint was planned to be analyzed only for participants at the China site in the Giltertinib PK cohort.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib | Ctrough Concentration of Gilteritinib | C26D1 | 264 ng/mL | Standard Deviation 138 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C27D1 | 199 ng/mL | Standard Deviation 145 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C28D1 | 243 ng/mL | Standard Deviation 141 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C29D1 | 184 ng/mL | Standard Deviation 138 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C30D1 | 340 ng/mL | Standard Deviation 472 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C31D1 | 426 ng/mL | Standard Deviation 606 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C34D1 | 405 ng/mL | Standard Deviation 590 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C35D1 | 298 ng/mL | Standard Deviation 420 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C36D1 | 264 ng/mL | Standard Deviation 343 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C37D1 | 437 ng/mL | Standard Deviation 823 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C1D8 | 310 ng/mL | Standard Deviation 177 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | CID15 | 367 ng/mL | Standard Deviation 243 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C2D1 | 425 ng/mL | Standard Deviation 305 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C3D1 | 457 ng/mL | Standard Deviation 358 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C4D1 | 420 ng/mL | Standard Deviation 428 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C5D1 | 407 ng/mL | Standard Deviation 487 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C6D1 | 284 ng/mL | Standard Deviation 275 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C7D1 | 370 ng/mL | Standard Deviation 477 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C8D1 | 328 ng/mL | Standard Deviation 323 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C9D1 | 351 ng/mL | Standard Deviation 381 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C10D1 | 322 ng/mL | Standard Deviation 383 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C11D1 | 336 ng/mL | Standard Deviation 426 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C12D1 | 460 ng/mL | Standard Deviation 703 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C13D1 | 368 ng/mL | Standard Deviation 409 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C14D1 | 386 ng/mL | Standard Deviation 449 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C15D1 | 396 ng/mL | Standard Deviation 541 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C16D1 | 200 ng/mL | Standard Deviation 116 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C17D1 | 228 ng/mL | Standard Deviation 138 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C18D1 | 201 ng/mL | Standard Deviation 143 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C19D1 | 231 ng/mL | Standard Deviation 270 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C20D1 | 241 ng/mL | Standard Deviation 190 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C21D1 | 221 ng/mL | Standard Deviation 112 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C22D1 | 238 ng/mL | Standard Deviation 149 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C23D1 | 152 ng/mL | Standard Deviation 137 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C24D1 | 188 ng/mL | Standard Deviation 141 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C25D1 | 192 ng/mL | Standard Deviation 137 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C32D1 | 301 ng/mL | Standard Deviation 395 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C33D1 | 431 ng/mL | Standard Deviation 646 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C38D1 | 78.0 ng/mL | Standard Deviation 76.3 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C39D1 | 107 ng/mL | Standard Deviation 91.3 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C40D1 | 114 ng/mL | Standard Deviation 59.2 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C41D1 | 152 ng/mL | Standard Deviation 123 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C42D1 | 128 ng/mL | Standard Deviation 150 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C43D1 | 96.9 ng/mL | Standard Deviation 114 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C44D1 | 148 ng/mL | Standard Deviation 145 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C45D1 | 166 ng/mL | Standard Deviation 97.9 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C46D1 | 105 ng/mL | Standard Deviation 127 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C47D1 | 116 ng/mL | Standard Deviation 104 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C48D1 | 131 ng/mL | Standard Deviation 107 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C49D1 | 74.4 ng/mL | Standard Deviation 82 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C50D1 | 134 ng/mL | Standard Deviation 119 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C51D1 | 130 ng/mL | Standard Deviation 136 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C52D1 | 93.4 ng/mL | Standard Deviation 114 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C53D1 | 148 ng/mL | Standard Deviation 188 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C54D1 | 166 ng/mL | Standard Deviation 246 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C55D1 | 129 ng/mL | Standard Deviation 169 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C56D1 | 157 ng/mL | Standard Deviation 227 |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C57D1 | 380 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C58D1 | 338 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C59D1 | 451 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C60D1 | 362 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C61D1 | 292 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C62D1 | 287 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C63D1 | 411 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C65D1 | 362 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C67D1 | 326 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C68D1 | 584 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C69D1 | 345 ng/mL | — |
| Gilteritinib | Ctrough Concentration of Gilteritinib | C70D1 | 313 ng/mL | — |
Secondary
Duration of Composite Complete Remission (CRc)
Duration of CRc: time from date of achieving first CRc until date of first documented relapse for participants who achieved CRc. KM estimate was used for analysis. CRc: rate of all complete & incomplete remissions \[CR + CRp + CRi\]. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.
Time frame: From date of achieving CRc until date of confirmed relapse (maximum duration was 60 months)
Population: ITT. Participants with best overall response of CRc were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Duration of Composite Complete Remission (CRc) | 4.1 months |
| Salvage Chemotherapy | Duration of Composite Complete Remission (CRc) | NA months |
p-value: 0.5596995% CI: [0.209, 2.414]Log Rank
Secondary
Duration of CR
Duration of CR: time from the date of achieving first CR until date of first documented relapse for participants who achieved CR. KM estimate was used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. Relapse was defined as documentation of any of following events: * BM blasts ≥ 5% (not attributable to regenerating BM) * Reappearance or new appearance of extramedullary leukemia * Reappearance of significant numbers of peripheral blasts
Time frame: From date of achieving CR until date of confirmed relapse (maximum duration was 53.4 months )
Population: ITT. Participants with CR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Duration of CR | 24.0 months |
| Salvage Chemotherapy | Duration of CR | NA months |
p-value: 0.887195% CI: [0.131, 10.338]Log Rank
Secondary
Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh)
Duration of CR/CRh: time from date of achieving first CR/CRh until date of first documented relapse for participants who achieved CR/CRh. KM estimate was used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.
Time frame: From date of achieving CR/CRh until date of confirmed relapse (maximum duration was 58.1 months)
Population: ITT. Participants with CR/CRh were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh) | 5.6 months |
| Salvage Chemotherapy | Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh) | NA months |
p-value: 0.6626195% CI: [0.192, 13.048]Log Rank
Secondary
Duration Of Response (DOR)
DOR: time from date of first CRc (CR+CRp+CRi)/PR until date of first documented relapse for participants who achieved CRc or PR. KM estimate used for analysis. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate & total BM blasts of 5-25%. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts and increase in the percentage of blasts in the BM aspirate to \> 25%.
Time frame: From date of achieving CRc/PR until date of confirmed relapse (maximum duration was 52.1 months)
Population: ITT. Participants with best overall response of CRc/PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Duration Of Response (DOR) | 3.7 months |
| Salvage Chemotherapy | Duration Of Response (DOR) | NA months |
p-value: 0.5573195% CI: [0.286, 1.999]Log Rank
Secondary
Event-Free Survival (EFS)
EFS: time from the date of randomization until the date of documented relapse, treatment failure, death, reported off treatment relapse or new AML therapy start whichever occued first, including the long-term follow-up data. KM estimate was used for analysis. Relapse was defined as documentation of any of following events: * Bone marrow (BM) blasts ≥ 5% (not attributable to regenerating BM) * Reappearance or new appearance of extramedullary leukemia * Reappearance of significant numbers of peripheral blasts Treatment failure: Treatment failure was defined as participant who ends treatment without having a previous response of CR, CR with incomplete platelet recovery (CRp) and CR with incomplete hematological recover (CRi).
Time frame: From the date of randomization up to the date of documented relapse, treatment failure or death from any cause, off-treatment relapse and start of new AML therapy (up to approximately 74 months)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Event-Free Survival (EFS) | 2.1 months |
| Salvage Chemotherapy | Event-Free Survival (EFS) | 0.6 months |
p-value: 0.0000595% CI: [0.438, 0.792]Log Rank
Secondary
Leukemia-Fee Survival (LFS)
LFS: time from the date of first CRc (CR+CRp+CRi) until the date of documented relapse or death for participants who achieved CRc. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. Relapse: BM blasts ≥ 5%, reappearance or new appearance of extramedullary leukemia, reappearance of significant numbers of peripheral blasts.
Time frame: From first day of achieving first CRc to the first day of confirmed relapse/death (maximum duration was 60.0 months)
Population: ITT. Participants with best overall response of CRc were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Leukemia-Fee Survival (LFS) | 3.9 months |
| Salvage Chemotherapy | Leukemia-Fee Survival (LFS) | 6.9 months |
p-value: 0.5694495% CI: [0.494, 1.487]Log Rank
Secondary
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores
The ECOG Scale was used to assess performance status. Number of participants with each grade was reported. Grade Description: 0: Fully active, able to carry on all pre-disease performance without restriction. 1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. 2. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. 3. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5. Dead.
Time frame: Baseline, end of treatment visit (63 months)
Population: SAF population with available data at specified timepoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 1 at baseline | 65 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 0 at End of Treatment | 17 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 3 at baseline | 0 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 1 at End of Treatment | 36 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 0 at baseline | 35 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 2 at End of Treatment | 19 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 4 at baseline | 0 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 2 at baseline | 34 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 4 at End of Treatment | 1 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 5 at baseline | 0 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 5 at End of Treatment | 0 Participants |
| Gilteritinib | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 3 at End of Treatment | 10 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 5 at End of Treatment | 0 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 0 at baseline | 37 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 1 at baseline | 64 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 2 at baseline | 18 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 3 at baseline | 0 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 4 at baseline | 0 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 5 at baseline | 0 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 0 at End of Treatment | 26 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 1 at End of Treatment | 39 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 2 at End of Treatment | 21 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 3 at End of Treatment | 6 Participants |
| Salvage Chemotherapy | Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores | Grade 4 at End of Treatment | 2 Participants |
Secondary
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 was defined as an adverse event observed after starting administration of the study drug.
Time frame: From the date of first dose up to approximately 74 months
Population: Safety Analysis Set (SAF): The SAF consisted of all participants who received at least 1 dose of study treatment (gilteritinib or salvage chemotherapy).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 134 Participants |
| Salvage Chemotherapy | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 119 Participants |
Secondary
Percentage of Participants With Transfusion Conversion and Transfusion Maintenance
Transfusion conversion rate: Percentage of transfusion dependent participants at baseline period but became transfusion independent at post-baseline period divided by total participants who were transfusion dependent at baseline period. Transfusion maintenance rate: Percentage of transfusion independent participants at baseline period and still maintained transfusion independent at post-baseline period divided by total participants who were transfusion independent at baseline period. Baseline transfusion status: Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to first dose to 28 days after first dose; otherwise classified as transfusion dependent. Post baseline transfusion status: Participants on treatment ≥ 84 days were classified as transfusion independent, if consecutive 56 days without any RBC or platelet transfusion; otherwise classified as transfusion dependent
Time frame: Baseline up to approximately 74 months
Population: ITT population with available data at specified timepoint. This endpoint was planned to be analyzed only for Giltertinib arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gilteritinib | Percentage of Participants With Transfusion Conversion and Transfusion Maintenance | Transfusion Conversion Rate | 42.7 Percentage of participants |
| Gilteritinib | Percentage of Participants With Transfusion Conversion and Transfusion Maintenance | Transfusion Maintenance Rate | 70.8 Percentage of participants |
Secondary
Percentage of Participants With Transplantation Rate
Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.
Time frame: Baseline up to approximately 74 months
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gilteritinib | Percentage of Participants With Transplantation Rate | 22.6 Percentage of participants |
| Salvage Chemotherapy | Percentage of Participants With Transplantation Rate | 7.9 Percentage of participants |
p-value: 0.0005595% CI: [6.5, 22.8]Cochran-Mantel-Haenszel
Secondary
Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24)
AUC24 was derived from the PK samples collected.
Time frame: Cycle 1 Day 1(C1D1): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, Cycle 1 Day 15(C1D15): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose
Population: Pharmacokinetics Analysis Set (PKAS): The PKAS consisted of all participants who received at least 1 administration of study intervention for which at least 1 concentration data with time of dosing and sampling were available. This endpoint was planned to be analyzed only for participants in Giltertinib PK cohort which included 21 participants from six china sites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib | Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24) | C1D1 | 3230 nanogram*hour per milliliters(ng*h/mL) | Standard Deviation 1970 |
| Gilteritinib | Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24) | C1D15 | 10000 nanogram*hour per milliliters(ng*h/mL) | Standard Deviation 6670 |
Secondary
PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax)
Cmax was derived from the PK samples collected.
Time frame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose
Population: PKAS. This endpoint was planned to be analysed only for participants in Giltertinib PK cohort which included 21 participants from six china sites.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gilteritinib | PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax) | C1D1 | 206 ng/mL | Standard Deviation 112 |
| Gilteritinib | PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax) | C1D15 | 536 ng/mL | Standard Deviation 323 |
Secondary
PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax)
tmax was derived from the PK samples collected.
Time frame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose
Population: PKAS. This endpoint was planned to be analysed only for participants in Giltertinib PK cohort which included 21 participants from six china sites.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gilteritinib | PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax) | Cycle 1 Day 1 | 4.00 hours |
| Gilteritinib | PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax) | Cycle 1 Day 15 | 3.85 hours |
Secondary
PK of Gilteritinib: Observed Trough Concentration (Ctrough)
Ctrough was derived from the PK samples collected.
Time frame: Predose on C1D15
Population: PKAS with available data at timepoint were analyzed. This endpoint was planned to be analyzed only for participants at the China site in the Giltertinib PK cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gilteritinib | PK of Gilteritinib: Observed Trough Concentration (Ctrough) | 323 ng/mL | Standard Deviation 222 |
Secondary
Time to CR
Time to CR (TTCR) was defined as the time from the date of randomization until the date of first CR. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \< 5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia.
Time frame: From randomization until date of first CR (up to approximately 74 months)
Population: ITT population. Participants who achieved CR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Time to CR | 3.7 months |
| Salvage Chemotherapy | Time to CR | 1.1 months |
Secondary
Time to CRc
Time to CRc (TTCRc) was defined as the time from the date of randomization until the date of first CRc. CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery.
Time frame: From randomization until date of first CRc (up to approximately 74 months)
Population: ITT population. Participants who achieved CRc were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Time to CRc | 1.8 months |
| Salvage Chemotherapy | Time to CRc | 1.0 months |
Secondary
Time to CR/CRh
Time to CR/CRh (TTCRCRh) was defined as the time from the date of randomization until the date of first CR/CRh. CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRh was defined as a condition at the post baseline visit, having bone marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5x10\^9/L and platelets ≥ 50x10\^9/L, no evidence of extramedullary leukemia and cannot be classified as CR. The blast counts in peripheral blood was ≤ 2%.
Time frame: From randomization until date of first CR/CRh (up to approximately 74 months)
Population: ITT population. Participants who achieved CR/CRh were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Time to CR/CRh | 2.8 months |
| Salvage Chemotherapy | Time to CR/CRh | 1.1 months |
Secondary
Time to Response
Time to Response (TTR) was defined as the time from the date of randomization until the date of either first response (CRc or PR). CRc: Rate of all complete and incomplete remissions (CR + CRp +Cri) CR: morphologically leukemia-free state, with ANC\> 1x10\^9/L, platelet count ≥ 100x10\^9/L and normal marrow differential with \<5% blasts. They were RBC and platelet transfusion independent and no evidence of extramedullary leukemia. CRp: met all CR criteria except incomplete platelet recovery (\< 100x10\^9/L). CRi: met all CR criteria, except for incomplete hematological recovery with residual neutropenia \< 1x10\^9/L with or without complete platelet recovery. PR: condition with regeneration of normal hematopoietic cells in BM, no detectable blasts, ≥ 50% decrease of blasts in BM aspirate & total BM blasts of 5-25%.
Time frame: From randomization until date of first CRc or PR (up to approximately 74 months)
Population: ITT population. Participants who achieved CRc or PR were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Gilteritinib | Time to Response | 1.0 months |
| Salvage Chemotherapy | Time to Response | 1.0 months |