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Amino Acids

Etoposide

Cytarabine

Mitoxantrone

Fludarabine

Fludarabine phosphate

Azacitidine

Lenograstim

Etoposide phosphate

Gilteritinib

Idarubicin

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Enzyme Inhibitors

Antiviral Agents

Adjuvants, Immunologic

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Antibiotics, Antitubercular

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Participants received 120 mg dose (3 tablets of 40 mg) orally once a day in continuous 28-day cycles, at least 2 hours after or 1 hour before food. Gilteritinib treatment continued until participants met one of the treatment discontinuation criteria.

Participants received chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10 days. Participants on azacitidine received 75 mg/m\^2 daily by SC or IV injection for 7 days. Participants on LoDAC or azacitidine treatment continued until they met discontinuation criteria. Participants on MEC chemotherapy received mitoxantrone 8 mg/m\^2 daily by IV for 5 days, etoposide 100 mg/m\^2 daily by IV for 5 days and cytarabine 1000 mg/m\^2 daily by IV for 5 days (days 1-5). Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m\^2 daily by SC/IV for 5 days (days 1-5), fludarabine 30 mg/m\^2 daily by IV for 5 days (days 2-6), cytarabine 2000 mg/m\^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m\^2 daily by IV for 3 days (days 2-4). Participants receiving MEC or FLAG-IDA received 1 cycle of therapy and were assessed for response on or after day 15.

gilteritinib

subcutaneous (SC) or intravenous (IV) injection

LoDAC (Low Dose Cytarabine)

MEC (Mitoxantrone, Etoposide, Cytarabine)

SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection

FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)

Executive Medical Director

The purpose of this study is to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and to determine the efficacy of ASP2215 therapy as assessed by the rate of complete remission and complete remission with partial hematological recovery (CR/CRh) in these participants.

This study will also determine 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 may participate in this study. Participants will be randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants will enter the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen will be pre-selected for each participant; options will include low-dose cytarabine (LoDAC), azacitidine, mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC), or fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) with idarubicin (FLAG-IDA). The randomization will be stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles.

After treatment discontinuation, participants will have a pre-hematopoietic stem cell transplant (HSCT)/end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety, in which a telephone contact with the participant is sufficient unless any assessment must be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up will be done every 3 months up to 3 years from the participant's end-of-treatment visit.

A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation

A Phase 3 Open-Label, Multicenter, Randomized Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation

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 compounds 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. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

Overall survival was defined as the time from the date of randomization until the date of death from any cause (death date - randomization date + 1). For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - randomized date + 1). The date of last contact was the latest date that the participant was known to be alive by the cutoff date. The last contact date was derived for participants alive at the analysis cutoff date. Survival rate and 95% CI were estimated using the Kaplan-Meier method and the Greenwood formula.

The CR/CRh rate was defined as the number of participants who achieved either CR or CRh at any of the postbaseline visits divided by the number of participants in the analysis population.

EFS was defined as the time from the date of randomization until the date of documented relapse (excluding relapse after PR), treatment failure or death from any cause within 30 days after the last dose of study drug, whichever occurred first (earliest of \[relapse date, treatment failure date, death date\] - randomization date + 1). If a participant experienced relapse or death within 30 days after the last dose of study drug, the participant was defined as having an EFS event related to either "relapse" or "death", and the event date was the date of relapse or death. For a participant who was not known to have had a relapse or treatment failure or death event, EFS was censored at the date of last relapse-free disease assessment (last relapse-free disease assessment date - randomization date + 1). Data was estimated based on Kaplan-Meier estimates.

The CR rate was defined as the number of participants who achieved the best response of CR divided by the number of participants in the analysis population.

The LFS was defined as the time from the date of first CRc until the date of documented relapse (excluding relapse from PR) or death for participants who achieved CRc (relapse date or death date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1). For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc disease assessment date + 1).

Duration of remission included duration of composite complete remission (CRc), duration of complete remission (CR)/ complete remission with partial hematologic recovery (CRh), duration of CRh, duration of CR and duration of response (CRc + partial remission (PR). The duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse (i.e., the date of first NR after CRc or PR) for participants who achieved CRc or PR (relapse date - first CRc or PR disease assessment date + 1). Participants who died without report of relapse were considered nonevents and censored at their last relapse-free disease assessment date (last relapse-free disease assessment date - first CRc or PR disease assessment date + 1). Other participants who did not relapse during the study were considered nonevents and censored at the last relapse-free assessment date. Duration of CR was only applicable to participants with best overall response of CR.

CRc rate was defined as the number of participants who achieved the best response of CRc (CR,complete remission with incomplete platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi) divided by the number of participants in the analysis population.

Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.

The Brief Fatigue Inventory (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. The global BFI score will be calculated only if at least 5 of the 9 items are answered. A higher BFI fatigue score indicates worse outcome.

CRh rate was defined as the number of participants who achieved CRh at any of the postbaseline visits and did not have a best response of CR divided by the number of participants in the analysis population.

Transfusion conversion \& maintenance rate was defined for gilteritinib arm. Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to the first dose to 28 days after the first dose; otherwise they were classified as transfusion dependent at baseline. Participants were considered independent postbaseline if they had 1 consecutive 8 week period without any RBC or platelet transfusion from 29 days after the first dose until the last dose date. For participants who were on treatment ≤ 4 weeks or \> 4 weeks but \< 12 weeks and there was no RBC or platelet transfusion within postbaseline period, they were considered not evaluable; otherwise, they were considered postbaseline transfusion dependent. Transfusion conversion rate was defined for participants who had evaluable postbaseline transfusion status. Transfusion status (independent vs. dependent) at baseline and postbaseline was reported in a 2 by 2 contingency table.

A treatment-emergent adverse event (TEAE) was defined as an AE observed after starting administration of the study drug (gilteritinib or salvage chemotherapy). If the AE occurred on day 1 and the onset check box was marked "Onset after first dose of study drug" or the onset check box was left blank, then the AE was considered treatment emergent. If the AE occurred on day 1 and the onset check box was marked "Onset before first dose of study drug", then the AE was not considered treatment emergent. Majority of salvage chemotherapy participants finished the study by cycle 2 of treatment, the duration of exposure was longer in the gilteritinib arm compared with the salvage chemotherapy arm (126.00 \[4.0, 885.0\] days versus 28.0 \[5.0, 217.0\] days). The NCI-CTCAE is defined as National Cancer Institute-Common Terminology Criteria for Adverse Events.

Astellas Pharma Global Development, Inc.

Salvage Chemotherapy

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

Ethnicity

The category of "Other" includes those with cytogenetic risk status that cannot be categorized as favorable, intermediate or unfavorable.

Cytogenic Risk Status

ECOG performance status is a scale used to assess impact on daily activities. It is based on the investigator assessment. Scores range from 0 to 5, with 0-signifying fully active participant; 1-restricted in physically strenuous activity; 2-ambulatory and capable of all self-care, unable to work; 3-capable of only limited self-care, confined to bed more than 50% of waking hours; 4-completely disabled and 5-dead. Negative numerical score indicates an improvement and positive numerical score indicates a decline in participant's daily activities, indicating disease progression.

Baseline Eastern Cooperative Oncology Group (ECOG)

FLT3 Mutation Status by Central Testing by FLT3 CDx

Prior use of FLT3 inhibitor is defined as 'Yes' if participants received prior AML therapy of midostaurin, sorafenib or quizartinib; otherwise, prior use of FLT3 inhibitor is assigned as No.

Prior Use of FLT3 Inhibitor

Region

The analysis population was the ITT, with available data.

Baseline Body Surface Area (BSA)

Baseline Height

Baseline Weight

Primary refractory without HSCT

Relapse within 6 months after CRc and no HSCT

Relapse after 6 months after CRc and no HSCT

Relapse within 6 months after allogeneic HSCT

Relapse after 6 months after allogeneic HSCT

Response to First Line Therapy

High intensity chemotherapy

Low intensity chemotherapy

Preselected Salvage Chemotherapy

Primary refractory w/o HSCT, high intensity (IT)

Primary refractory w/o HSCT, low IT

Relapse w/I 6 mths after CRc and no HSCT, high IT

Relapse w/I 6 mths after CRc and no HSCT low IT

Relapse after 6 mths after CRc and no HSCT high IT

Relapse w/I 6 mths after allogeneic HSCT low IT

Relapse w/I 6 mths after allogeneic HSCT high IT

Relapse after 6 mths after allogeneic HSCT high IT

Relapse after 6 mths after CRc and no HSCT low IT

Relapse after 6 mths after allogeneic HSCT low IT

Baseline stratification factors. HSCT is hematopoietic stem cell transplant. CRc is composite complete remission.

Response to First Line Therapy-Preselected Salvage Chemotherapy

The analysis population was the Intention to Treatment (ITT), which consisted of all randomized participants.

Clinical Trial Disclosure

Stratified analysis where tratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT.

The analysis population was the Intention to Treatment (ITT) which consisted of all randomized participants.

Duration of Overall Survival (OS)

CR/CRh rate

CR rate

CRh rate

The analysis population was the response analysis set (RAS) which consisted of participants who were who were at least 112 days past the first dose of gilteritinib or randomization (for participants who did not receive gilteritinib). The participants were analyzed based on the randomized treatments.

Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm

Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT

Duration of Event-Free Survival (EFS)

Based on stratified Cochran-Mantel-Haenszel test. Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT. Treatment difference = gilteritinib -chemotherapy.

Percentage of Participants With Complete Remission (CR) Rate

The LFS was analyzed for participants who achieved remission using the stratified log-rank test with strata to control for response to first-line AML therapy and preselected salvage chemotherapy. Duration of LFS was based on Kaplan-Meier estimates.

The analysis population was the ITT, with participants with best response of CRc.

Duration of Leukemia-Free Survival (LFS)

The analysis population was the ITT, Duration of CR was only applicable to participants with best overall response of CR.

Duration of Remission

Treatment difference = gilteritinib - chemotherapy. The 95% CIs were asymptotic confidence limits using the normal approximation to the binomial distribution.

Percentage of Participants With Composite Complete Remission (CRc Rate)

Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant

C1D8: Using analysis of covariance (ANCOVA) including treatment as a fixed factor, baseline score, response to first-line AML therapy and preselected salvage chemotherapy per IRT as covariates. Least Square (LS) Mean difference was estimated using chemotherapy as control.

C2D1: Using analysis of covariance (ANCOVA) including treatment as a fixed factor, baseline score, response to first-line AML therapy and preselected salvage chemotherapy per IRT as covariates. Least Square (LS) Mean difference was estimated using chemotherapy as control.

Cycle 1 day 8 (C1D8)

Cycle 2 day 1 (C2D1)

The analysis population was the ITT, with participants with data at baseline.

Change From Baseline in Brief Fatigue Inventory (BFI)

Based on a stratified Cochran-Mantel-Haenszel test. Stratification factors were response to first-line AML therapy and preselected salvage chemotherapy per IRT. Pooled strata were used as shown in Table 12.3.3.2.

Treatment differences were adjusted based on pooled strata. Treatment difference = gilteritinib 120 mg - chemotherapy.

Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)

Baseline Independent/ Post baseline Independent

Baseline Independent/Post baseline Dependent

Baseline Independent/Post baseline Not Evaluable

Baseline Dependent/Post baseline Independent

Baseline Dependent/Post baseline Dependent

Baseline Dependent/Post baseline Not Evaluable

The analysis population was the ITT, with participants who had evaluable postbaseline transfusion status.

Percentage of Participants Who Achieved Transfusion Conversion and Maintenance

Drug-related TEAE

Serious TEAE

Drug-related serious TEAE

TEAE leading to death

Drug-related TEAE leading to death

TEAE leading to withdrawal of treatment

Drug-related TEAE lead withdrawal of treatment

NCI-CTCAE Grade 3 or higher TEAE

Drug-related Grade 3 or higher TEAE

Death

The analysis population was the safety analysis set (SAF), which consisted of participants who received who received at least 1 dose of study drug (gilteritinib or salvage chemotherapy).

Number of Participants With Adverse Events

Overall Study

Decitabine

Subjects received 40 mg dose orally once a day in continuous 28-day cycles, at least 2 hours before and after food. Clifutinib treatment continued until sujects met one of the treatment discontinuation criteria.

Subjects received chemotherapy in 28-day cycles. Subjects on Low-Dose Cytarabine (LoDAC) received 10 mg of cytarabine twice daily by subcutaneous (SC) or intravenous (IV) injection for 10\~14 days. Subjects on azacitidine received 75 mg/m\^2 daily by SC for 7 days. Subjects on decitabine received 20 mg/m\^2 daily by IV injection for 5 days. Subjects on LoDAC or azacitidine or decitabine treatment continued until they met discontinuation criteria. Subjects on Ara-C±IDA chemotherapy received cytarabine 1\~3 g/m\^2 daily by IV for 3 days and idarubicin 10 mg/m\^2 daily by IV for 3 days. Participants on FLAG-IDA chemotherapy received G-CSF 300 μg/m\^2 daily by SC for 6 days (days 1-6), fludarabine 30 mg/m\^2 daily by IV for 5 days (days 2-6), cytarabine 1\~2 g/m\^2 daily by IV for 5 days (days 2-6) and idarubicin 10 mg/m\^2 daily by IV for 3 days (days 2-4). Subjects receiving Ara-C±IDA or FLAG-IDA received 1 cycle of therapy and were assessed for response on day 28+/-2 days.

Clifutinib

LoDAC

Ara-C±IDA

FLAG-IDA

Lejie Zheng, MSc

Jie Jin, Doctor

Jie Jin, MD, PhD

A randomized，multicenter, open-label Phase III, clinical study is conducted to evaluate the clinical benefit Clifutinib in Chinese patients with relapsed/ refractory (R/R) FLT3-mutated AML as shown with overall survival compared to salvage chemotherapy, and also to investigate the efficacy of Clifutinib as assessed by CR/CRh rate in these subjects.

Subjects who are at least 18 years and above at the time of signing informed consent may participate in this study. Subjects will be randomized in a 2:1 ratio to receive Clifutinib or salvage chemotherapy. Subjects will enter the screening period up to 28 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen will be pre-selected for each subjects; options will include low-dose cytarabine (LoDAC), azacitidine, decitabine, Ara-C±IDA or FLAG±IDA. The randomization will be stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles.

After treatment discontinuation, participants will have a end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety. After that, long term follow-up will be done every 90 days.

HEC73543 Versus Salvage Chemotherapy in R/R FLT3-ITD AML

HEC73543 Versus Salvage Chemotherapy in Relapsed or Refractory FLT3-ITD Acute Myeloid Leukemia: a Multicenter, Open-label, Randomized Phase 3 Trial

Overall survival was defined as the time from the date of randomization until the date of death from any cause

The CR/CRh rate was defined as the number of subjects who achieved either CR or CRh at any of the postbaseline visits divided by the number of subjects in the analysis population

EFS was defined as the time from the date of randomization until the date of documented relapse, treatment failure, new anti-leukemia therapy or death from any cause

The CR rate was defined as the number of subjects who achieved the best response of CR divided by the number of subjects in the analysis population

CRc rate was defined as the number of subjects who achieved the best response of CRc (CR, CRh or CRi divided by the number of subjects in the analysis population

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation	NCT02421939	Leukemia, Acute...	gilteritinib LoDAC (Low Dose... Azacitidine MEC (Mitoxantro... FLAG-IDA (Granu...	18 Years -	Astellas Pharma Inc
HEC73543 Versus Salvage Chemotherapy in R/R FLT3-ITD AML	NCT05586074	Leukemia, Acute...	Clifutinib LoDAC Azacitidine Decitabine Ara-C±IDA FLAG-IDA	18 Years -	Sunshine Lake Pharma Co., Ltd.
A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation	NCT02421939	Leukemia, Acute...	gilteritinib LoDAC (Low Dose... Azacitidine MEC (Mitoxantro... FLAG-IDA (Granu...	18 Years -	Astellas Pharma Inc
A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation	NCT02421939	Leukemia, Acute...	gilteritinib LoDAC (Low Dose... Azacitidine MEC (Mitoxantro... FLAG-IDA (Granu...	18 Years -	Astellas Pharma Inc

Spots Global Cancer Trial Database for leukemia, acute myeloid (aml)