2215-CL-0301

Astellas Pharma Global Development, Inc.

1 Astellas Way, Northbrook, United States, 60062

Clinical Transparency, Astellas Pharma Global Development, Inc., +1 800-888-770, astellas.resultsdisclosure@astellas.com

Clinical Transparency, Astellas Pharma Global Development, Inc., +1 800-888-7704, astellas.resultsdisclosure@astellas.com

No

No

No

Final

25 Feb 2025

No

Yes

25 Feb 2025

No

The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated acute myeloid leukemia (AML) who were refractory to or had relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy, and determined 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 also determined the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

20 Oct 2015

Yes

Yes

Belgium: 1

Canada: 4

France: 13

Germany: 15

Israel: 7

Italy: 33

Japan: 48

Korea, Republic of: 28

Poland: 5

Spain: 30

Taiwan: 18

Türkiye: 1

United Kingdom: 6

United States: 162

371

97

0

0

0

0

0

0

216

154

1

Randomization Period: Up to 3 years

Randomised - controlled

Yes

Gilteritinib

ASP2215 XOSPATA®

Tablet

Oral use

120mg tablet orally once a day

MEC (Mitoxantrone, Etoposide, Cytarabine)

Solution for injection

Intravenous use

Mitoxantrone: 8 mg/m^2 daily by IV Etoposide: 100mg/m^2 daily Cytarabine: 1000 mg/m^2 daily by IV

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

Solution for injection

Intravascular use , Subcutaneous use

G-CSF: 300 μg/m^2 daily by SC/IV Fludarabine: 30 mg/m^2 daily by IV Cytarabine: 2000 mg/m^2 daily by IV Idarubicin 10mg/m^2 daily by IV for 3 days.

LoDAC (Low Dose Cytarabine)

Solution for injection

Intravenous use, Subcutaneous use

20 mg of cytarabine twice daily by SC or IV injection

Azacitidine

Solution for injection

Intravenous use, Subcutaneous use

75 mg/m^2 daily by SC or IV injection

Long-term follow-up: up to 3 years

Randomised - controlled

No

Gilteritinib

ASP2215 XOSPATA®

Tablet

Oral use

120mg tablet orally once a day

MEC (Mitoxantrone, Etoposide, Cytarabine)

Solution for injection

Intravenous use

Mitoxantrone: 8 mg/m^2 daily by IV Etoposide: 100mg/m^2 daily Cytarabine: 1000 mg/m^2 daily by IV

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

Solution for injection

Intravascular use , Subcutaneous use

G-CSF: 300 μg/m^2 daily by SC/IV Fludarabine: 30 mg/m^2 daily by IV Cytarabine: 2000 mg/m^2 daily by IV Idarubicin 10mg/m^2 daily by IV for 3 days.

LoDAC (Low Dose Cytarabine)

Solution for injection

Intravenous use, Subcutaneous use

20 mg of cytarabine twice daily by SC or IV injection

Azacitidine

Solution for injection

Intravenous use, Subcutaneous use

75 mg/m^2 daily by SC or IV injection

Gilteritinib

Salvage Chemotherapy

Gilteritinib

Salvage Chemotherapy

Gilteritinib

Salvage Chemotherapy

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

Primary

From randomization to until the date of death from any cause (median time of follow-up for OS was 17.8 months)

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

Gilteritinib v Salvage Chemotherapy

371

Pre-specified

0.637

2-sided

CR/CRh rate: achieved either CR or CRh divided by number of participants in analysis population. CR: bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). No evidence of extramedullary leukemia. CRh: CRh: if they had marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5 x 10^9/L and platelets ≥ 50 x 10^9/L, no evidence of extramedullary leukemia and could not be classified as CR. Analysis population was the response analysis set (RAS) with participants who were 112 days past the first dose of gilteritinib/randomization. Participants were analyzed based on randomized treatments.

Primary

From the date of randomization up to at least 112 days

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. CR: For participants to be classified as being in CR, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. The analysis population was the ITT.

Secondary

From the date of randomization up to at least 6 months

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.

Gilteritinib v Salvage Chemotherapy

371

Pre-specified

10.6

2-sided

EFS: time from randomization date up to date of documented relapse (excluding relapse after PR)/ treatment failure (failure to achieve CR, CRp, CRi /PR) /death, whichever occurred first. Relapse: leukemic blasts in peripheral blood 5/ ≥ 25% blasts in bone marrow (BM) aspirate due to no other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10^9/L, platelet count ≥100x10^9/L, normal marrow differential with <5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp:achieved CR except incomplete platelet recovery (<100x 0^9/L). CRi:criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia <1x10^9/L with /without complete platelet recovery. PR:BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts & decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present. ITT.

Secondary

From the date of randomization until the date of documented relapse, treatment failure or death from any cause (median time of follow-up was 17.8 months)

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

Gilteritinib v Salvage Chemotherapy

251

Pre-specified

0.793

2-sided

Duration of remission included duration of CRc, CR/CRh, CRh, CR, CRi, CRp (defined as time from date of first CRc until date of first documented relapse for participants who achieved CRc, CR/CRh, CRh, CR, CRi, CRp respectively) & duration of response (CRc + PR). CRc:achieved CR, CRp or CRi at the visit. CR:BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10^9/L, platelet count ≥100x10^9/L, normal marrow differential with <5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp:achieved CR except incomplete platelet recovery (<100x 0^9/L). CRi:criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia <1x10^9/L with /without complete platelet recovery. PR:BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts and decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present. participants with best overall CR response analysed.

Secondary

From the date of either first CRc or PR until the date of documented relapse for participants who achieved CRc or PR (median time of follow-up was 17.8 months)

Gilteritinib v Salvage Chemotherapy

65

Pre-specified

0.206

2-sided

LFS: time from the date of first CRc until the date of documented relapse or death for subjects who achieve CRc. For a subject who is not known to have relapsed or died, LFS is censored on the date of last relapse-free disease assessment date. CRc: achieved CR, CRp or CRi. Relapse: leukemic blasts in peripheral blood/≥ 25% blasts in bone marrow (BM) aspirate not due to any other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC 1x10^9/L, platelet count ≥10 x10^9/L, normal marrow differential with < 5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (<100x10^9/L). CRi : criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with /without complete platelet recovery. The analysis population was the ITT, with participants with best response of CRc.

Secondary

From the date of first CRc until the date of documented relapse or death for participants who achieved CRc (median time of follow-up was 17.8 months)

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.

Gilteritinib v Salvage Chemotherapy

161

Pre-specified

0.889

2-sided

CRc rate: Number of participants with best response of CRc (CR,complete remission with incomplete platelet recovery [CRp] or complete remission with incomplete hematologic recovery [CRi]) divided by number of participants in the analysis population. CRc : Participants who achieved CR, CRp or CRi at a post-baseline visit. CR: Participants having bone marrow regenerating normal hematopoietic cells, a morphologic leukemia-free state, an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, and being RBC and platelet transfusion independent with no evidence of extramedullary leukemia at a post-baseline visit. CRp: Participants achieving CR except for incomplete platelet recovery (< 100 x 10^9/L) at a post-baseline visit. CRi : Participants, who fulfilled all criteria for CR except incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery at a post-baseline visit. ITT population analysed.

Secondary

From the date of randomization up to at least 6 months

Treatment difference = gilteritinib – chemotherapy. The95% CIs were asymptotic confidence limits using the normal approximation to the binomial distribution.

Gilteritinib v Salvage Chemotherapy

371

Pre-specified

32.5

2-sided

BFI was a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during 24 hours. There are 9 items on the scale. The first three questions asked 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. Next six questions asked participants to rate fatigue interference with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). Global fatigue score can be obtained by averaging all items on the BFI. Total score range is 0-10 with a higher BFI fatigue score indicating worse outcome. Global BFI score was calculated only if at least 5 of the 9 items were answered. Analysis population: ITT, with participants with data at baseline. SAP pre-specified that 95% Confidence Interval would not be analyzed for this endpoint, 2-Sides (-99999, 99999) was entered to remove validation error.

Secondary

Baseline and cycle 1 day 8 and cycle 2 day 1

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.

Gilteritinib v Salvage Chemotherapy

324

Pre-specified

0.1574

2-sided

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.

Gilteritinib v Salvage Chemotherapy

324

Pre-specified

-1.2567

2-sided

Transplantation rate was defined as the percentage of participants who underwent Hematopoietic stem cell transplant (HSCT) during the study period. The analysis population is the ITT.

Secondary

From the date of randomization until end of study (median time of follow-up was 17.8 months)

Gilteritinib v Salvage Chemotherapy

371

Pre-specified

10.2

2-sided

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. CR: For participants to be classified as being in CR at a post-baseline visit, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with < 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh:At a post baseline visit, participantss were classified as CRh if they had marrow blasts < 5%, partial hematologic recovery ANC ≥ 0.5 x 10^9/L and platelets ≥ 50 x 10^9/L, no evidence of extramedullary leukemia and could not be classified as CR. The analysis population was the ITT.

Secondary

From the date of randomization up to at least 6 months

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.

Gilteritinib v Salvage Chemotherapy

371

Pre-specified

18.6

2-sided

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.

Secondary

From 29 days post first dose of study drug until last dose (median treatment duration was (126.00 [4.0, 885.0])

An AE was defined as any untoward medical occurrence in a participant, temporally associated with study drug use, whether/not related to it, such as any unfavorable/unintended sign (including abnormal laboratory finding), symptom/disease (new/exacerbated). Treatment-emergent adverse event (TEAE) : AEs observed after starting administration of study drug Serious AEs (SAEs): AEs which caused death, were life-threatening, resulted in persistent/significant disability/incapacity or disruption of the ability to conduct normal life functions, congenital anomaly, birth defect, required inpatient hospitalization/led to prolongation of hospitalization. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. Safety analysis set (SAF), with participants who received who received at least 1 dose of study drug was analysed.

Secondary

From first dose of study drug up to 30 days after the last dose of study drug (median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)

From first dose of study drug up to 30 days after the last dose of study drug (median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days).

The SAF consisted of all participants who received at least dose of study treatment (gilteritinib or salvage chemotherapy).

v23

Gilteritinib

Salvage Chemotherapy