2215-cl-0304

Astellas Pharma Global Development, Inc

1 Astellas Way Northbrook, Illinois, United States, 60062

Clinical Transparency, Astellas Pharma Global Development, Inc. (APGD), +1 8008887704, astellas.resultsdisclosure@astellas.com

Clinical Transparency, Astellas Pharma Global Development, Inc, +1 8008887704, astellas.resultsdisclosure@astellas.com

No

No

No

Final

09 May 2023

No

Yes

09 May 2023

No

The primary objective of this study was to compare relapse free survival (RFS) between participants with FMS-like tyrosine kinase 3/Internal tandem duplication (FLT3/ITD) acute myeloid leukemia (AML) in first morphologic complete remission (CR1) who underwent hematopoietic stem cell transplantation (HSCT) and were randomized to receive gilteritinib or placebo beginning after the time of engraftment for a 2-year period.

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.

16 Aug 2017

Yes

Yes

Australia: 9

Belgium: 3

Canada: 2

Denmark: 6

France: 5

Germany: 22

Greece: 3

Italy: 15

Japan: 57

Korea, Republic of: 29

New Zealand: 2

Poland: 2

Spain: 12

Taiwan: 13

United Kingdom: 24

United States: 152

356

68

0

0

0

0

0

0

299

57

0

Overall (overall period)

Randomised - controlled

Yes

Gilteritinib

ASP2215

Tablet

Oral use

Participants received gilteritinib 120 mg (three tablets of 40 mg) orally

Placebo

Tablet

Oral use

Participants received gilteritinib matching placebo orally

Gilteritinib

Placebo

Gilteritinib

Placebo

RFS was defined as the time from the date of randomization until the date of documented morphological relapse, or death from any cause, whichever occurred first. Morphological relapse was defined as documentation of any of the following events: ● BM blasts ≥ 5% (not attributable to regenerating BM) ● Any circulating blasts (not attributable to regenerating BM or growth factors) ● Presence of extramedullary blast foci per Revised International Working Group (RIWG) criteria ● The earliest date of any of the relapse event were used for RFS. Intention-to-Treat (ITT) population: All randomized participants were included in this population. Here “99999” indicated that data was not estimable because less than 50% of participants had event (data was estimated using Kaplan-Meier [KM] and it requires at least 50% of event to be able to calculate time using KM).

Primary

From the date of randomization up to 64 months and 22 days

Gilteritinib v Placebo

356

Pre-specified

0.679

2-sided

OS was defined as the time from randomization until the date of death from any cause (death date – first dose 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 – first dose date + 1). ITT population. Here “99999” indicated that data was not estimable because less than 50% of participants had event (data was estimated using KM and it requires at least 50% of event to be able to calculate time using KM).

Secondary

From the date of randomization until 65 months

Gilteritinib v Placebo

356

Pre-specified

0.846

2-sided

An Adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, and which did not have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease (new or exacerbated) temporally associated with the use of a medicinal product, whether considered related to the medicinal product. TEAE defined as an AE event observed through 30 days after the last dose. Safety Analysis Population: consisted of all participants who took at least 1 dose of study drug (gilteritinib or placebo).

Secondary

From the date of randomization through 30 days after the last dose, up to 25 months and 22 days

KPS scores of participants were reported. KPS was a standard way of measuring ability of cancer participants to perform ordinary tasks. It was 11 level score which ranged between 0-100%. 100 =Normal, no complaints, no evidence of disease 90 =Able to carry on normal activity, minor signs or symptoms of disease 80 =Normal activity with effort, some signs or symptoms of disease 70 =Care for self, unable to carry on normal activity or to do work 60 =Required occasional assistance but was able to care for most of his needs 50 =Required considerable assistance & frequent medical care 40 =Disabled, required special care & assistance 30 = Severely disabled, hospitalization indicated, although death not imminent 20 =Very sick, hospitalization necessary, active supportive treatment necessary 10 =moribund fatal processes progressing rapidly 0 =Dead. Safety Analysis Population with available data was analyzed.

Secondary

Baseline, month 24

NRM was defined as death from any cause other than relapse or disease progression (DP). Relapse was defined as documentation of any of the following events: ● BM blasts ≥ 5% (not attributable to regenerating BM) ● Any circulating blasts (not attributable to regenerating BM or growth factors) ● Presence of extramedullary blast foci per RIWG criteria ● The earliest date of any of the relapse event were used for RFS. DP: >=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of >=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. Incidence of NRM was estimated using the cumulative incidence function, treating relapse/progression as a competing risk. ITT population

Secondary

From the date of randomization up to 64 months and 22 days

Gilteritinib v Placebo

356

Pre-specified

2.308

2-sided

EFS: Time from date of randomization until documented relapse, or premature discontinuation of treatment or initiation of other anti-leukemic treatment or death from any cause, whichever occurred first. Relapse was defined as documentation of any of following events: ● BM blasts ≥ 5% (not attributable to regenerating BM) ● Any circulating blasts (not attributable to regenerating BM or growth factors) ● Presence of extramedullary blast foci per RIWG criteria ● The earliest date of any of relapse event were used for RFS. Anti-leukemic treatment was defined as hypomethylating agents, chemotherapy, oral anticancer agents, Donor lymphocyte infusion (DLI) or cellular therapies given because of detectable disease, not meeting R-IWG criteria for relapse. ITT population. Here “99999” indicated that data was not estimable because less than 50% of participants had event (data was estimated using KM and it requires at least 50% of event to be able to calculate time using KM).

Secondary

From the date of randomization until 65 months

Gilteritinib v Placebo

356

Pre-specified

0.93

2-sided

The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV aGVHD were reported, treating death prior to aGVHD as the competing risk. It was graded according to diagnosis and severity scoring used by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The acute GVHD algorithm calculated the grade based on the organ (skin, gastrointestinal (GI)and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD was defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD was stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV was stage 4 of skin, or stage 4 of liver. Grade IV was the worst outcome. Treatment emergent was defined as an event observed through 30 days after the last dose ITT population

Secondary

From the date of randomization up to 6 months

Gilteritinib v Placebo

356

Pre-specified

1.4254

2-sided

Gilteritinib v Placebo

356

Pre-specified

0.8938

2-sided

Chronic GVHD was graded according to diagnosis and severity scoring from the National Institute of Health (NIH) 2014 Consensus Criteria. Eight organs - skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia were scored on a 0-3 scale to reflect degree of chronic GVHD involvement, where 0 = no involvement/no symptoms & 3 indicated the worst symptom. This system staged severity in each individual organ, and then a global score defined as mild, moderate or severe, based on number of organs involved and organ severity score was calculated. The cumulative incidence of chronic GVHD (mild, moderate, severe) at 12 months after randomization was reported, treating death prior to chronic GVHD as the competing risk. Treatment emergent was defined as an event observed through 30 days after the last dose. ITT population

Secondary

From the date of randomization up to 12 months

Gilteritinib v Placebo

356

Pre-specified

1.236

2-sided

Chronic GVHD was graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria. Eight organs- skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are scored on a 0-3 scale to reflect degree of chronic GVHD involvement where 0 = no involvement/no symptoms & 3 indicated the worst symptom. This system staged severity in each individual organ, and then a global score defined as mild, moderate or severe, based on number of organs involved and organ severity score was calculated. The cumulative incidence of chronic GVHD (mild, moderate, severe) at 24 months after randomization was reported, treating death prior to chronic GVHD as the competing risk. Treatment emergent was defined as an event observed through 30 days after the last dose. ITT population

Secondary

From the date of randomization up to 24 months

Gilteritinib v Placebo

356

Pre-specified

1.236

2-sided

The presence of MRD was considered Detectable in participants who were FLT3/ITD MRD undetectable prior to randomization if log10-transformed overall FLT3/ITD mutation ratio greater than -4 otherwise presence of MRD was considered Not Detectable. Participants who had detectable FLT3/ITD MRD prior to randomization were considered eradicated if log10-transformed overall FLT3/ITD mutation ratio ≤ -4. Incidence of MRD Eradication and Detection were estimated using the cumulative incidence function, treating death during MRD assessment period without documentation of MRD event as competing risk. ITT population with available data was analyzed. Here 99999 indicated data not estimable because no participants in Placebo group were followed up to 1 year (cumulative incidence function requires at least 1 participant to calculate the cumulative incidence rate).

Secondary

From the date of randomization up to 64 months and 22 days

Gilteritinib v Placebo

327

Pre-specified

0.7073

2-sided

Gilteritinib v Placebo

327

Pre-specified

3.4537

2-sided

Cumulative incidence of relapse was reported, treating death in remission as a competing risk. Relapse was defined as documentation of any of the following events: ● BM blasts ≥ 5% (not attributable to regenerating BM) ● Any circulating blasts (not attributable to regenerating BM or growth factors) ● Presence of extramedullary blast foci per RIWG criteria ● The earliest date of any of the relapse event were used for RFS. ITT population

Secondary

From the date of randomization up to 64 months and 22 days

Gilteritinib v Placebo

356

Pre-specified

0.3729

2-sided

Severity of Infection was assessed based on the following criteria: Grade 1-Mild Asymptomatic or mild symptoms, clinical or diagnostic observations noted intervention not indicated. Grade 2-Moderate Local or noninvasive intervention indicated. Grade 3-Severe Medically significant but not immediately life threatening, hospitalization or prolonged hospitalization. Grade 4-Life Threatening Life threatening consequences, urgent intervention indicated. Grade 5-Death related to the AE. Cumulative incidence of grade 3 to 5 infections were reported, treating death (grade 5) as a competing event. Treatment emergent was defined as an event observed through 30 days after the last dose. ITT population

Secondary

From the date of randomization through 30 days after the last dose, up to 25 months and 22 days

Gilteritinib v Placebo

356

Pre-specified

1.4848

2-sided

All-cause mortality: From the date of randomization up to 64 months and 22 days Adverse events: From the date of randomization through 30 days after the last dose, up to 25 months and 22 days

Safety Analysis Population. All-cause mortality, serious & other adverse events were reported for all randomized participants who received actual dose of study drug during study. 1 participant randomized to placebo received gilteritinib, was included under gilteritinib arm. 1 participant randomized to gilteritinib arm did not receive any treatment.

v23

Placebo

Gilteritinib