Clinical trial NCT02421939: A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia, Acute Myeloid (AML)
Keywords: ASP2215
Relapsed Acute Myeloid Leukemia
FLT3 Mutation
gilteritinib
Refractory Acute Myeloid Leukemia
Acute Myeloid Leukemia (AML)
XOSPATA®
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2015-04-21
Enrollment: 371
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

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.

Primary outcomes:
measure: Duration of Overall Survival (OS)
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm
timeFrame: From randomization until the data cut-off date 04 Aug 2017, the 142 patients included in the primary analysis of CR/CRh rate were followed up at least 112 days
Secondary outcomes:
measure: Duration of Event-Free Survival (EFS)
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Percentage of Participants With Complete Remission (CR) Rate
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, all participants included in the primary analysis of CR rate were followed up at least 6 months
measure: Duration of Leukemia-Free Survival (LFS)
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Duration of Remission
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Percentage of Participants With Composite Complete Remission (CRc Rate)
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Change From Baseline in Brief Fatigue Inventory (BFI)
timeFrame: Baseline and cycle 1, day 8 and cycle 2 day 1 (up to data cut off date of 17 Sep 2018)
measure: Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
measure: Percentage of Participants Who Achieved Transfusion Conversion and Maintenance
timeFrame: From randomization until the data cut-off date of 17 Sep 2018, median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)
measure: Number of Participants With Adverse Events
timeFrame: 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)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Site US10011
state: Alabama
city: Los Angeles
country: United States
facility: Site US10012
state: California
city: Orange
country: United States
facility: Site US10076
state: California
city: San Francisco
country: United States
facility: Site US10073
state: California
city: New Haven
country: United States
facility: Site US10067
state: Connecticut
city: Gainesville
country: United States
facility: Site US10045
state: Florida
city: Atlanta
country: United States
facility: Site US10081
state: Georgia
city: Chicago
country: United States
facility: Site US10006
state: Illinois
city: Westwood
country: United States
facility: Site US10075
state: Kansas
city: Louisville
country: United States
facility: Site US10074
state: Kentucky
city: New Orleans
country: United States
facility: Site US10048
state: Louisiana
city: Baltimore
country: United States
facility: Site US10005
state: Maryland
city: Boston
country: United States
facility: Site US10034
state: Massachusetts
city: Boston
country: United States
facility: Site US10022
state: Massachusetts
city: Boston
country: United States
facility: Site US10085
state: Massachusetts
city: Detroit
country: United States
facility: Site US10087
state: Michigan
city: Minneapolis
country: United States
facility: Site US10057
state: Minnesota
city: Lebanon
country: United States
facility: Site US10023
state: New Hampshire
city: Hackensack
country: United States
facility: Site US10027
state: New Jersey
city: New Brunswick
country: United States
facility: Site US10077
state: New Jersey
city: Buffalo
country: United States
facility: Site US10001
state: New York
city: New York
country: United States
facility: Site US10037
state: New York
city: New York
country: United States
facility: Site US10008
state: New York
city: New York
country: United States
facility: Site US10013
state: New York
city: New York
country: United States
facility: Site US10072
state: New York
city: Syracuse
country: United States
facility: Site US10046
state: New York
city: Durham
country: United States
facility: Site US10024
state: North Carolina
city: Winston-Salem
country: United States
facility: Site US10078
state: North Carolina
city: Cleveland
country: United States
facility: Site US10044
state: Ohio
city: Columbus
country: United States
facility: Site US10084
state: Ohio
city: Oklahoma City
country: United States
facility: Site US10058
state: Oklahoma
city: Hershey
country: United States
facility: Site US10041
state: Pennsylvania
city: Philadelphia
country: United States
facility: Site US10010
state: Pennsylvania
city: Philadelphia
country: United States
facility: Site US10080
state: Pennsylvania
city: Charleston
country: United States
facility: Site US10014
state: South Carolina
city: Nashville
country: United States
facility: Site US10063
state: Tennessee
city: Milwaukee
country: United States
facility: Site US10035
state: Wisconsin
city: Yvoir
country: Belgium
facility: Site BE32002
city: Edmonton
country: Canada
facility: Site CA15004
state: Alberta
city: Hamilton
country: Canada
facility: Site CA15001
state: Ontario
city: Toronto
country: Canada
facility: Site CA15015
state: Ontario
city: Montreal
country: Canada
facility: Site CA15003
state: Quebec
city: Brest
country: France
facility: Site FR33013
city: Le Chesnay Cedex
country: France
facility: Site FR33002
city: Lille
country: France
facility: Site FR33010
city: Pessac
country: France
facility: Site FR33009
city: Rennes
country: France
facility: Site FR33014
city: Toulouse
country: France
facility: Site FR33008
city: Dresden
country: Germany
facility: Site DE49009
city: Leipzig
country: Germany
facility: Site DE49011
city: Marburg
country: Germany
facility: Site DE49003
city: Munchen
country: Germany
facility: Site DE49002
city: Tubingen
country: Germany
facility: Site DE49010
city: Ashkelon
country: Israel
facility: Site IL97201
city: Haifa
country: Israel
facility: Site IL97209
city: Jerusalem
country: Israel
facility: Site IL97203
city: Jerusalem
country: Israel
facility: Site IL97210
city: Petah Tikva
country: Israel
facility: Site IL97206
city: Rehovot
country: Israel
facility: Site IL97208
city: Bologna
country: Italy
facility: Site IT39005
city: Brescia
country: Italy
facility: Site IT39010
city: Milan
country: Italy
facility: Site IT39001
city: Palermo
country: Italy
facility: Site IT39004
city: Pavia
country: Italy
facility: Site IT39011
city: Roma
country: Italy
facility: Site IT39007
city: Varese
country: Italy
facility: Site IT39002
city: Nagoya
country: Japan
facility: Site JP81002
state: Aichi
city: Narita
country: Japan
facility: Site JP81010
state: Chiba
city: Yoshida-gun
country: Japan
facility: Site JP81026
state: Fukui
city: Sapporo
country: Japan
facility: Site JP81016
state: Hokkaido
city: Kobe
country: Japan
facility: Site JP81018
state: Hyogo
city: Tsukuba
country: Japan
facility: Site JP81017
state: Ibaraki
city: Isehara
country: Japan
facility: Site JP81009
state: Kanagawa
city: Yokohama
country: Japan
facility: Site JP81006
state: Kanagawa
city: Sendai
country: Japan
facility: Site JP81012
state: Miyagi
city: Kurashiki
country: Japan
facility: Site JP81007
state: Okayama
city: Osakasayama
country: Japan
facility: Site JP81014
state: Osaka
city: Kawagoe
country: Japan
facility: Site JP81020
state: Saitama
city: Shimotsuke
country: Japan
facility: Site JP81027
state: Tochigi
city: Chuo-ku
country: Japan
facility: Site JP81005
state: Tokyo
city: Shinagawa-ku
country: Japan
facility: Site JP81004
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Site JP81022
state: Tokyo
city: Akita
country: Japan
facility: Site JP81023
city: Aomori
country: Japan
facility: Site JP81021
city: Kumamoto
country: Japan
facility: Site JP81013
city: Kyoto
country: Japan
facility: Site JP81025
city: Nagasaki
country: Japan
facility: Site JP81008
city: Okayama
country: Japan
facility: Site JP81024
city: Osaka
country: Japan
facility: Site JP81011
city: Suwon-si
country: Korea, Republic of
facility: Site KR82005
state: Gyeonggi-do
city: Busan
country: Korea, Republic of
facility: Site KR82010
city: Goyang
country: Korea, Republic of
facility: Site KR82009
city: Jeollanam-do
country: Korea, Republic of
facility: Site KR82003
city: Seoul
country: Korea, Republic of
facility: Site KR82007
city: Seoul
country: Korea, Republic of
facility: Site KR82004
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82002
city: Seoul
country: Korea, Republic of
facility: Site KR82008
city: Seoul
country: Korea, Republic of
facility: Site KR82011
city: Gdansk
country: Poland
facility: Site PL48002
city: Opole
country: Poland
facility: Site PL48005
city: Wroclaw
country: Poland
facility: Site PL48004
city: Badalona
country: Spain
facility: Site ES34009
city: Barcelona
country: Spain
facility: Site ES34011
city: Barcelona
country: Spain
facility: Site ES34012
city: Barcelona
country: Spain
facility: Site ES34010
city: Girona
country: Spain
facility: Site ES34016
city: L'Hospitalet de Llobregat
country: Spain
facility: Site ES34005
city: Salamanca
country: Spain
facility: Site ES34014
city: Valencia
country: Spain
facility: Site ES34017
city: Kaohsiung
country: Taiwan
facility: Site TW88606
city: Kaohsiung
country: Taiwan
facility: Site TW88604
city: Taichung City
country: Taiwan
facility: Site TW88609
city: Taichung
country: Taiwan
facility: Site TW88608
city: Tainan
country: Taiwan
facility: Site TW88601
city: Taipei
country: Taiwan
facility: Site TW88603
city: Taipei
country: Taiwan
facility: Site TW88610
city: Taipei
country: Taiwan
facility: Site TW88611
city: Taipei
country: Taiwan
facility: Site TW88602
city: Taoyuan
country: Taiwan
facility: Site TW88605
city: Ankara
country: Turkey
facility: Site TR90001
city: Ankara
country: Turkey
facility: Site TR90004
city: Bournemouth
country: United Kingdom
facility: Site GB44014
city: Harrow
country: United Kingdom
facility: Site GB44013
city: Manchester
country: United Kingdom
facility: Site GB44003
city: Plymouth
country: United Kingdom
facility: Site GB44015
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.