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

NCT ID: NCT02421939

Last Updated: 2025-12-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 371 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-20
• Study Completion Date: 2025-02-25

Brief Summary

The purpose of this study was to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated 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.

Detailed Description

Participants considered an adult according to local regulations at the time of signing informed consent participated in this study. Participants were randomized in a 2:1 ratio to receive ASP2215 or salvage chemotherapy. Participants entered the screening period up to 14 days prior to the start of treatment. Prior to randomization, a salvage chemotherapy regimen was pre-selected for each participant; options included 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 was stratified by response to first-line therapy and pre-selected salvage chemotherapy. Participants were administered treatment over continuous 28-day cycles. After treatment discontinuation, participants had 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 was sufficient unless any assessment had to be repeated for resolution of treatment-related adverse events (AEs). After that, long term follow-up was done every 3 months up to 3 years from the participant's end-of-treatment visit.

Conditions

Leukemia, Acute Myeloid (AML)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Gilteritinib

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.

Group Type: EXPERIMENTAL

gilteritinib

Intervention Type: DRUG

tablet, oral

Salvage Chemotherapy

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.

Group Type: ACTIVE_COMPARATOR

LoDAC (Low Dose Cytarabine)

Intervention Type: DRUG

subcutaneous (SC) or intravenous (IV) injection

Azacitidine

Intervention Type: DRUG

SC or IV injection

MEC (Mitoxantrone, Etoposide, Cytarabine)

Intervention Type: DRUG

IV injection

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

Intervention Type: DRUG

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

Interventions

gilteritinib

tablet, oral

Intervention Type: DRUG

LoDAC (Low Dose Cytarabine)

subcutaneous (SC) or intravenous (IV) injection

Intervention Type: DRUG

Azacitidine

SC or IV injection

Intervention Type: DRUG

MEC (Mitoxantrone, Etoposide, Cytarabine)

IV injection

Intervention Type: DRUG

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

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

Intervention Type: DRUG

Other Intervention Names

ASP2215; XOSPATA®

Eligibility Criteria

Inclusion Criteria

• Participant has a diagnosis of primary acute myeloid leukemia (AML) or AML secondary to myelodysplastic syndrome (MDS) according to WHO classification (2008) as determined by pathology review at the treating institute.
• Participant is refractory to or relapsed after first-line AML therapy (with or without hematopoietic stem cell transplant (HSCT)).

• Refractory to first-line AML therapy is defined as:

1. Participant did not achieve complete remission/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp) under initial therapy. A Participant eligible for standard therapy must receive at least one 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 one complete block of induction therapy seen as the optimum choice of therapy to induce remission for this subject.

• Untreated first hematologic relapse is defined as:

1. Participant must have achieved a CR/CRi/CRp (criteria as defined by [Cheson et al, 2003], see Section 5.3) with first line treatment and has hematologic relapse.

• Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A Participant with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Participants can be enrolled from a local test result if they have any of the following FLT3 mutations: FLT3 internal tandem duplication (ITD), FLT3 tyrosine kinase domain (TKD)/D835 or FLT3- TKD/I836.
• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Participant is eligible for pre-selected salvage chemotherapy.
• Participant must meet the following criteria as indicated on the clinical laboratory tests:

• Serum aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal (ULN)
• Serum total bilirubin ≤ 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
• Participant is suitable for oral administration of study drug.
• Female Participant must either:

• Be of non-child bearing potential:

1. post-menopausal (defined as at least 1 year without any menses) prior to Screening, or

2. documented as surgically sterile (at least 1 month prior to Screening)

• Or, if of childbearing potential,

1. Agree not to try to become pregnant during the study and for 180 days after the final study administration

2. And have a negative urine pregnancy test at Screening

3. And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at Screening and throughout the study period and for 180 days after the final study drug administration.

• Female Participant must agree not to breastfeed at Screening and throughout the study period and for 60 days after the final study drug administration.
• Female Participant must not donate ova starting at Screening and throughout the study period and for 180 days after the final study drug administration.
• Male Participant and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at Screening and continue throughout the study period and for 120 days after the final study drug administration.
• Male Participant must not donate sperm starting at Screening and throughout the study period and 120 days after the final study drug administration.
• Participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria

• Participant was diagnosed as acute promyelocytic leukemia (APL).
• Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
• Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
• Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease
• Participant has clinically active central nervous system leukemia.
• Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
• Participant has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation, and/or maintenance).
• Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation (DIC).
• Participant has had major surgery within 4 weeks prior to the first study dose.
• Participant has radiation therapy within 4 weeks prior to the first study dose.
• Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or Participant with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
• Participant requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP)3A.
• Participants with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading.
• Participants with Long QT Syndrome at Screening.
• Participants with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]).
• Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of P glycoprotein (P-gp) with the exception of drugs that are considered absolutely essential for the care of the subject.
• Participant requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
• Participant has an active uncontrolled infection.
• Participant is known to have human immunodeficiency virus infection.
• Participant has active hepatitis B or C, or other active hepatic disorder.
• Participant has any condition which makes the Participant unsuitable for study participation.
• Participant has active clinically significant GVHD or is on treatment with systemic corticosteroids for GVHD.
• Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Astellas Pharma Global Development, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Executive Medical Director

Role: STUDY_DIRECTOR

Astellas Pharma Global Development, Inc.

Locations

Site US10011

Birmingham, Alabama, United States

Site US10012

Los Angeles, California, United States

Site US10076

Orange, California, United States

Site US10073

San Francisco, California, United States

Site US10067

New Haven, Connecticut, United States

Site US10045

Gainesville, Florida, United States

Site US10081

Atlanta, Georgia, United States

Site US10006

Chicago, Illinois, United States

Site US10075

Westwood, Kansas, United States

Site US10074

Louisville, Kentucky, United States

Site US10048

New Orleans, Louisiana, United States

Site US10005

Baltimore, Maryland, United States

Site US10034

Boston, Massachusetts, United States

Site US10022

Boston, Massachusetts, United States

Site US10085

Boston, Massachusetts, United States

Site US10087

Detroit, Michigan, United States

Site US10057

Minneapolis, Minnesota, United States

Site US10023

Lebanon, New Hampshire, United States

Site US10027

Hackensack, New Jersey, United States

Site US10077

New Brunswick, New Jersey, United States

Site US10001

Buffalo, New York, United States

Site US10037

New York, New York, United States

Site US10008

New York, New York, United States

Site US10013

New York, New York, United States

Site US10072

New York, New York, United States

Site US10046

Syracuse, New York, United States

Site US10024

Durham, North Carolina, United States

Site US10078

Winston-Salem, North Carolina, United States

Site US10044

Cleveland, Ohio, United States

Site US10084

Columbus, Ohio, United States

Site US10058

Oklahoma City, Oklahoma, United States

Site US10041

Hershey, Pennsylvania, United States

Site US10010

Philadelphia, Pennsylvania, United States

Site US10080

Philadelphia, Pennsylvania, United States

Site US10014

Charleston, South Carolina, United States

Site US10063

Nashville, Tennessee, United States

Site US10035

Milwaukee, Wisconsin, United States

Site BE32002

Yvoir, , Belgium

Site CA15004

Edmonton, Alberta, Canada

Site CA15001

Hamilton, Ontario, Canada

Site CA15015

Toronto, Ontario, Canada

Site CA15003

Montreal, Quebec, Canada

Site FR33013

Brest, , France

Site FR33002

Le Chesnay, , France

Site FR33010

Lille, , France

Site FR33009

Pessac, , France

Site FR33014

Rennes, , France

Site FR33008

Toulouse, , France

Site DE49009

Dresden, , Germany

Site DE49011

Leipzig, , Germany

Site DE49003

Marburg, , Germany

Site DE49002

München, , Germany

Site DE49010

Tübingen, , Germany

Site IL97201

Ashkelon, , Israel

Site IL97209

Haifa, , Israel

Site IL97203

Jerusalem, , Israel

Site IL97210

Jerusalem, , Israel

Site IL97206

Petah Tikva, , Israel

Site IL97208

Rehovot, , Israel

Site IT39005

Bologna, , Italy

Site IT39010

Brescia, , Italy

Site IT39001

Milan, , Italy

Site IT39004

Palermo, , Italy

Site IT39011

Pavia, , Italy

Site IT39007

Roma, , Italy

Site IT39002

Varese, , Italy

Site JP81002

Nagoya, Aichi-ken, Japan

Site JP81010

Narita, Chiba, Japan

Site JP81026

Yoshida-gun, Fukui, Japan

Site JP81016

Sapporo, Hokkaido, Japan

Site JP81018

Kobe, Hyōgo, Japan

Site JP81017

Tsukuba, Ibaraki, Japan

Site JP81009

Isehara, Kanagawa, Japan

Site JP81006

Yokohama, Kanagawa, Japan

Site JP81012

Sendai, Miyagi, Japan

Site JP81007

Kurashiki, Okayama-ken, Japan

Site JP81014

Sayama, Osaka, Japan

Site JP81020

Kawagoe, Saitama, Japan

Site JP81027

Shimotsuke, Tochigi, Japan

Site JP81005

Chuo-ku, Tokyo, Japan

Site JP81004

Shinagawa-ku, Tokyo, Japan

Site JP81022

Shinjuku-ku, Tokyo, Japan

Site JP81023

Akita, , Japan

Site JP81021

Aomori, , Japan

Site JP81013

Kumamoto, , Japan

Site JP81025

Kyoto, , Japan

Site JP81008

Nagasaki, , Japan

Site JP81024

Okayama, , Japan

Site JP81011

Osaka, , Japan

Site PL48002

Gdansk, , Poland

Site PL48005

Opole, , Poland

Site PL48004

Wroclaw, , Poland

Site KR82005

Suwon, Gyeonggi-do, South Korea

Site KR82010

Busan, , South Korea

Site KR82009

Goyang, , South Korea

Site KR82003

Jeollanam-do, , South Korea

Site KR82007

Seoul, , South Korea

Site KR82004

Seoul, , South Korea

Site KR82001

Seoul, , South Korea

Site KR82002

Seoul, , South Korea

Site KR82008

Seoul, , South Korea

Site KR82011

Seoul, , South Korea

Site ES34009

Badalona, , Spain

Site ES34011

Barcelona, , Spain

Site ES34012

Barcelona, , Spain

Site ES34010

Barcelona, , Spain

Site ES34016

Girona, , Spain

Site ES34005

L'Hospitalet de Llobregat, , Spain

Site ES34014

Salamanca, , Spain

Site ES34017

Valencia, , Spain

Site TW88606

Kaohsiung City, , Taiwan

Site TW88604

Kaohsiung City, , Taiwan

Site TW88608

Taichung, , Taiwan

Site TW88609

Taichung, , Taiwan

Site TW88601

Tainan, , Taiwan

Site TW88603

Taipei, , Taiwan

Site TW88610

Taipei, , Taiwan

Site TW88611

Taipei, , Taiwan

Site TW88602

Taipei, , Taiwan

Site TW88605

Taoyuan District, , Taiwan

Site TR90001

Ankara, , Turkey (Türkiye)

Site TR90004

Ankara, , Turkey (Türkiye)

Site GB44014

Bournemouth, , United Kingdom

Site GB44013

Harrow, , United Kingdom

Site GB44003

Manchester, , United Kingdom

Site GB44015

Plymouth, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Israel; Italy; Japan; Poland; South Korea; Spain; Taiwan; Turkey (Türkiye); United Kingdom

References

Ritchie EK, Cella D, Fabbiano F, Pigneux A, Kanda Y, Ivanescu C, Pandya BJ, Shah MV. Patient-reported outcomes from the phase 3 ADMIRAL trial in patients with FLT3-mutated relapsed/refractory AML. Leuk Lymphoma. 2023 May;64(5):938-950. doi: 10.1080/10428194.2023.2186731. Epub 2023 Apr 5.

Reference Type: DERIVED

PMID: 37019445 (View on PubMed)

Smith CC, Levis MJ, Perl AE, Hill JE, Rosales M, Bahceci E. Molecular profile of FLT3-mutated relapsed/refractory patients with AML in the phase 3 ADMIRAL study of gilteritinib. Blood Adv. 2022 Apr 12;6(7):2144-2155. doi: 10.1182/bloodadvances.2021006489.

Reference Type: DERIVED

PMID: 35130342 (View on PubMed)

Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Recher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, Levis MJ. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial. Blood. 2022 Jun 9;139(23):3366-3375. doi: 10.1182/blood.2021011583.

Reference Type: DERIVED

PMID: 35081255 (View on PubMed)

Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, Levis MJ. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. N Engl J Med. 2019 Oct 31;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.

Reference Type: DERIVED

PMID: 31665578 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.clinicaltrials.astellas.com/study/2215-CL-0301

Link to results and other applicable study documents on the Astellas Clinical Trials website

https://www.trialsummaries.com/Study/StudyDetails?id=14515&tenant=MT_AST_9011

Link to plain language summary of the study on the Trial Results Summaries website

Other Identifiers

2015-000140-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2215-CL-0301

Identifier Type: -

Identifier Source: org_study_id