A Phase 3 interventional study of Gilteritinib and Cytarabine in AML With FLT3 Mutation, sponsored by Astellas Pharma Inc. Completed at 49 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-22.
Sponsored by Astellas Pharma Inc · Phase 3, Interventional, and Treatment
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.
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.
Inclusion Criteria:
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:
Participant must meet the following criteria as indicated on the clinical laboratory tests:
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:
Exclusion Criteria:
Exclusion Criteria for COE:
Participant will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or when the participant is evaluated for eligibility to participate in the COE portion of the study.
Participants received 120 milligrams (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.
Drug: Gilteritinib
Participants received salvage chemotherapy in continuous 28-day cycles per institutional guidelines:LoDAC:20mg cytarabine twice daily SC/IV for 10 days. MEC:mitoxantrone 6 milligrams per square meter(mg/m\^2)/day IV for 5 days (days 1 to 5), etoposide 100mg/m\^2/day IV for 5 days (days 1 to 5), cytarabine 1000mg/m\^2/day IV for 5 days (days 1 to 5). FLAG: granulocyte colony-stimulating factor (G-CSF) 300 micrograms per square meter (μg/m\^2) per day SC/IV for 5 days (days 1 to 5), fludarabine 30mg/m\^2/day IV for 5 days (days 2 to 6), cytarabine 2000mg/m\^2/day IV for 5 days (days 2 to 6). Participants meeting treatment discontinuation criteria, entered long-term follow-up, for up to 3 years from end of treatment visit/until study discontinuation. Based on interim analysis outcome, at investigators discretion, treatment period participants had option to enter crossover extension to receive 120mg gilteritinib, orally, once daily in continuous 28-day cycles until treatment discontinuation.
Drug: Cytarabine · Drug: Mitoxantrone · Drug: Etoposide · Drug: G-CSF · Drug: Fludarabine
Tablet administered orally once daily.
Also known as: ASP2215
Once/twice daily Intravenously (IV)/subcutaneously (SC).
Once daily IV injection.
Once daily IV injection.
Once daily IV/SC injection.
Once daily IV injection.
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)
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)
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
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 )
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)
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)
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)
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
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
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)
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
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)
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)
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)
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)
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
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
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)
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
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)
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
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
PK of Gilteritinib: Observed Trough Concentration (Ctrough)
Ctrough was derived from the PK samples collected.
Time frame: Predose on C1D15
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
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
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.
| Milestone | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Started | 137 | 139 |
| Lodac | 0 | 27 |
| Mec | 0 | 42 |
| Flag | 0 | 70 |
| Chinese pk cohort | 21 | 0 |
| Completed | 0 | 26 |
| Not completed | 137 | 113 |
| Withdrew: Adverse event | 8 | 9 |
| Withdrew: Death | 19 | 8 |
| Withdrew: Miscellaneous | 12 | 0 |
| Withdrew: Disease relapse | 41 | 5 |
| Withdrew: Physician decision | 5 | 10 |
| Withdrew: Withdrawal by subject | 10 | 28 |
| Withdrew: Protocol violation | 4 | 1 |
| Withdrew: Progressive disease | 18 | 9 |
| Withdrew: Lack of efficacy | 20 | 43 |
| Milestone | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Started | 100 | 105 |
| Completed | 9 | 12 |
| Not completed | 91 | 93 |
| Withdrew: Miscellaneous | 4 | 3 |
| Withdrew: Withdrawal by subject | 5 | 8 |
| Withdrew: Lost to follow-up | 6 | 7 |
| Withdrew: Death | 76 | 75 |
| Milestone | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Started | 0 | 0 |
| Completed | 0 | 0 |
| Not completed | 0 | 0 |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Overall Survival (OS) | 10.3 (8.8 to 12.7) | 5.4 (4.1 to 8.1) |
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).
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Event-Free Survival (EFS) | 2.1 (0.1 to 3.2) | 0.6 (0.2 to 1.2) |
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.
| Percentage of participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Complete Remission (CR) Rate | 20.4 (14.0 to 28.2) | 11.5 (6.7 to 18.0) |
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
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Duration of CR | 24.0 (4.6 to NA) | NA (1.0 to NA) |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Duration of Composite Complete Remission (CRc) | 4.1 (2.8 to 5.6) | NA (NA to NA) |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh) | 5.6 (2.8 to 24.0) | NA (NA to NA) |
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%.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Duration Of Response (DOR) | 3.7 (2.5 to 4.7) | NA (1.2 to NA) |
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%.
| Percentage of participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| CR/CRh Rate | 32.1 (24.4 to 40.6) | 14.4 (9.0 to 21.3) |
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.
| Percentage of participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| CR | 20.4 | 11.5 |
| CRp | 13.1 | 0.7 |
| CRi | 19.7 | 10.1 |
| PR | 14.6 | 5.0 |
| NR | 27.7 | 34.5 |
| NE | 4.4 | 38.1 |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Leukemia-Fee Survival (LFS) | 3.9 (2.8 to 5.4) | 6.9 (2.9 to 10.4) |
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.
| Percentage of participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Composite Complete Remission (CRc) | 53.3 (44.6 to 61.9) | 22.3 (15.7 to 30.1) |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Time to CRc | 1.8 (1 to 8) | 1.0 (1 to 2) |
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.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Time to CR | 3.7 (1 to 19) | 1.1 (1 to 2) |
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%.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Time to Response | 1.0 (1 to 7) | 1.0 (1 to 2) |
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%.
| months | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Time to CR/CRh | 2.8 (1 to 11) | 1.1 (1 to 2) |
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 | Gilteritinib |
|---|---|
| Transfusion Conversion Rate | 42.7 |
| Transfusion Maintenance Rate | 70.8 |
Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.
| Percentage of participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Percentage of Participants With Transplantation Rate | 22.6 (15.9 to 30.6) | 7.9 (4.0 to 13.7) |
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.
| Scores on scale | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Change From Baseline in Brief Fatigue Inventory (BFI) | 1.42 ± 2.99 | 0.75 ± 2.92 |
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.
| Participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | 134 | 119 |
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.
| Participants | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Grade 0 at baseline | 35 | 37 |
| Grade 1 at baseline | 65 | 64 |
| Grade 2 at baseline | 34 | 18 |
| Grade 3 at baseline | 0 | 0 |
| Grade 4 at baseline | 0 | 0 |
| Grade 5 at baseline | 0 | 0 |
| Grade 0 at End of Treatment | 17 | 26 |
| Grade 1 at End of Treatment | 36 | 39 |
| Grade 2 at End of Treatment | 19 | 21 |
| Grade 3 at End of Treatment | 10 | 6 |
| Grade 4 at End of Treatment | 1 | 2 |
| Grade 5 at End of Treatment | 0 | 0 |
AUC24 was derived from the PK samples collected.
| nanogram*hour per milliliters(ng*h/mL) | Gilteritinib |
|---|---|
| C1D1 | 3230 ± 1970 |
| C1D15 | 10000 ± 6670 |
Cmax was derived from the PK samples collected.
| ng/mL | Gilteritinib |
|---|---|
| C1D1 | 206 ± 112 |
| C1D15 | 536 ± 323 |
Ctrough was derived from the PK samples collected.
| ng/mL | Gilteritinib |
|---|---|
| PK of Gilteritinib: Observed Trough Concentration (Ctrough) | 323 ± 222 |
tmax was derived from the PK samples collected.
| hours | Gilteritinib |
|---|---|
| Cycle 1 Day 1 | 4.00 (2.00 to 24.1) |
| Cycle 1 Day 15 | 3.85 (1.00 to 24.3) |
Concentrations below the lower limit of quantification (0.5 ng/mL) were set to zero.
| ng/mL | Gilteritinib |
|---|---|
| C1D8 | 310 ± 177 |
| CID15 | 367 ± 243 |
| C2D1 | 425 ± 305 |
| C3D1 | 457 ± 358 |
| C4D1 | 420 ± 428 |
| C5D1 | 407 ± 487 |
| C6D1 | 284 ± 275 |
| C7D1 | 370 ± 477 |
| C8D1 | 328 ± 323 |
| C9D1 | 351 ± 381 |
| C10D1 | 322 ± 383 |
| C11D1 | 336 ± 426 |
| C12D1 | 460 ± 703 |
| C13D1 | 368 ± 409 |
| C14D1 | 386 ± 449 |
| C15D1 | 396 ± 541 |
| C16D1 | 200 ± 116 |
| C17D1 | 228 ± 138 |
| C18D1 | 201 ± 143 |
| C19D1 | 231 ± 270 |
| C20D1 | 241 ± 190 |
| C21D1 | 221 ± 112 |
| C22D1 | 238 ± 149 |
| C23D1 | 152 ± 137 |
| C24D1 | 188 ± 141 |
| C25D1 | 192 ± 137 |
| C26D1 | 264 ± 138 |
| C27D1 | 199 ± 145 |
| C28D1 | 243 ± 141 |
| C29D1 | 184 ± 138 |
| C30D1 | 340 ± 472 |
| C31D1 | 426 ± 606 |
| C32D1 | 301 ± 395 |
| C33D1 | 431 ± 646 |
| C34D1 | 405 ± 590 |
| C35D1 | 298 ± 420 |
| C36D1 | 264 ± 343 |
| C37D1 | 437 ± 823 |
| C38D1 | 78.0 ± 76.3 |
| C39D1 | 107 ± 91.3 |
| C40D1 | 114 ± 59.2 |
| C41D1 | 152 ± 123 |
| C42D1 | 128 ± 150 |
| C43D1 | 96.9 ± 114 |
| C44D1 | 148 ± 145 |
| C45D1 | 166 ± 97.9 |
| C46D1 | 105 ± 127 |
| C47D1 | 116 ± 104 |
| C48D1 | 131 ± 107 |
| C49D1 | 74.4 ± 82.0 |
| C50D1 | 134 ± 119 |
| C51D1 | 130 ± 136 |
| C52D1 | 93.4 ± 114 |
| C53D1 | 148 ± 188 |
| C54D1 | 166 ± 246 |
| C55D1 | 129 ± 169 |
| C56D1 | 157 ± 227 |
| C57D1 | 380 |
| C58D1 | 338 |
| C59D1 | 451 |
| C60D1 | 362 |
| C61D1 | 292 |
| C62D1 | 287 |
| C63D1 | 411 |
| C65D1 | 362 |
| C67D1 | 326 |
| C68D1 | 584 |
| C69D1 | 345 |
| C70D1 | 313 |
Collected over All-cause mortality: From randomization up to 74 months AEs: From first dose up to 74 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Gilteritinib | 97/137 (70.8%) | 102/134 (76.1%) | 133/134 (99.3%) |
| Salvage Chemotherapy | 85/139 (61.2%) | 71/119 (59.7%) | 113/119 (95%) |
| Event | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| Febrile neutropeniaBlood and lymphatic system disorders | 29/134 | 25/119 |
| PneumoniaInfections and infestations | 24/134 | 8/119 |
| SepsisInfections and infestations | 9/134 | 15/119 |
| AnaemiaBlood and lymphatic system disorders | 14/134 | 1/119 |
| PyrexiaGeneral disorders | 12/134 | 0/119 |
| ThrombocytopeniaBlood and lymphatic system disorders | 11/134 | 1/119 |
| Neutropenic sepsisInfections and infestations | 8/134 | 4/119 |
| Skin infectionInfections and infestations | 7/134 | 0/119 |
| Septic shockInfections and infestations | 5/134 | 5/119 |
| Acute respiratory failureRespiratory, thoracic and mediastinal disorders | 0/134 | 5/119 |
| Event | Gilteritinib | Salvage Chemotherapy |
|---|---|---|
| AnaemiaBlood and lymphatic system disorders | 99/134 | 79/119 |
| Blood lactate dehydrogenase increasedInvestigations | 61/134 | 22/119 |
| White blood cell count decreasedInvestigations | 55/134 | 51/119 |
| HypokalaemiaMetabolism and nutrition disorders | 57/134 | 45/119 |
| Platelet count decreasedInvestigations | 55/134 | 50/119 |
| ThrombocytopeniaBlood and lymphatic system disorders | 56/134 | 44/119 |
| Aspartate aminotransferase increasedInvestigations | 56/134 | 19/119 |
| PyrexiaGeneral disorders | 54/134 | 45/119 |
| Neutrophil count decreasedInvestigations | 51/134 | 44/119 |
| Alanine aminotransferase increasedInvestigations | 49/134 | 23/119 |
Intent-to-treat analysis Set (ITT) : The ITT consisted of all participants who were randomized.
| Age, Continuous(Years) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| Mean | 46.9 ± 16.2 | 46.2 ± 15.1 | 46.6 ± 15.7 |
| Sex: Female, Male(Participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| Female | 76 | 70 | 146 |
| Male | 61 | 69 | 130 |
| Ethnicity (NIH/OMB)(Participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 136 | 139 | 275 |
| Unknown or Not Reported | 1 | 0 | 1 |
| Race (NIH/OMB)(Participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 123 | 120 | 243 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 14 | 19 | 33 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| China | 90 | 92 | 182 |
| Russia | 14 | 19 | 33 |
| Malaysia | 15 | 14 | 29 |
| Thailand | 14 | 10 | 24 |
| Singapore | 4 | 4 | 8 |
| Response to First-Line Therapy(Participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| Relapse within 6 months after allogeneic HSCT | 1 | 4 | 5 |
| Relapse after 6 months after allogeneic HSCT | 2 | 2 | 4 |
| Primary refractory without HSCT | 80 | 81 | 161 |
| Relapse within 6 months after CRc and no HSCT | 31 | 29 | 60 |
| Relapse after 6 months after CRc and no HSCT | 23 | 23 | 46 |
| Preselected Salvage Chemotherapy(Participants) | Gilteritinib | Salvage Chemotherapy | Total |
|---|---|---|---|
| High intensity chemotherapy | 110 | 112 | 222 |
| Low intensity chemotherapy | 27 | 27 | 54 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
Supporting information: Study protocol, Sap, Csr
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