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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02421939




Registration number
NCT02421939
Ethics application status
Date submitted
16/04/2015
Date registered
21/04/2015

Titles & IDs
Public title
A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation
Scientific 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
Secondary ID [1] 0 0
2015-000140-42
Secondary ID [2] 0 0
2215-CL-0301
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Leukemia, Acute Myeloid (AML) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional(has expanded access)
Description of intervention(s) / exposure
Treatment: Drugs - gilteritinib
Treatment: Drugs - LoDAC (Low Dose Cytarabine)
Treatment: Drugs - Azacitidine
Treatment: Drugs - MEC (Mitoxantrone, Etoposide, Cytarabine)
Treatment: Drugs - FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)

Experimental: 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.

Active comparator: 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.


Treatment: Drugs: gilteritinib
tablet, oral

Treatment: Drugs: LoDAC (Low Dose Cytarabine)
subcutaneous (SC) or intravenous (IV) injection

Treatment: Drugs: Azacitidine
SC or IV injection

Treatment: Drugs: MEC (Mitoxantrone, Etoposide, Cytarabine)
IV injection

Treatment: Drugs: FLAG-IDA (Granulocyte-Colony Stimulating Factor (G-CSF), Fludarabine, Cytarabine, Idarubicin)
SC (G-CSF) and IV (Fludarabine, Cytarabine, Idarubicin) injection
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Duration of Overall Survival (OS)
Timepoint [1] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Primary outcome [2] 0 0
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh) in the Gilteritinib Arm
Timepoint [2] 0 0
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 outcome [1] 0 0
Duration of Event-Free Survival (EFS)
Timepoint [1] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [2] 0 0
Percentage of Participants With Complete Remission (CR) Rate
Timepoint [2] 0 0
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
Secondary outcome [3] 0 0
Duration of Leukemia-Free Survival (LFS)
Timepoint [3] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [4] 0 0
Duration of Remission
Timepoint [4] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [5] 0 0
Percentage of Participants With Composite Complete Remission (CRc Rate)
Timepoint [5] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [6] 0 0
Percentage of Participants Who Underwent Hematopoietic Stem Cell Transplant
Timepoint [6] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [7] 0 0
Change From Baseline in Brief Fatigue Inventory (BFI)
Timepoint [7] 0 0
Baseline and cycle 1, day 8 and cycle 2 day 1 (up to data cut off date of 17 Sep 2018)
Secondary outcome [8] 0 0
Percentage of Participants With Complete Remission (CR) With Partial Hematological Recovery (CRh)
Timepoint [8] 0 0
From randomization until the data cut-off date of 17 Sep 2018, median time of follow-up for OS was 17.8 months
Secondary outcome [9] 0 0
Percentage of Participants Who Achieved Transfusion Conversion and Maintenance
Timepoint [9] 0 0
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)
Secondary outcome [10] 0 0
Number of Participants With Adverse Events
Timepoint [10] 0 0
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)

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/10/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/12/2024
Actual
Sample size
Target
Accrual to date
Final
371
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
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United States of America
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Alabama
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California
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Connecticut
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Florida
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Georgia
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Roma
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Aichi
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Chiba
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Nagasaki
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Seoul
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Opole
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Barcelona
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Girona
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L'Hospitalet de Llobregat
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Salamanca
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Valencia
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Taiwan
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Kaohsiung
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Taichung City
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Taichung
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Taipei
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Taoyuan
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Turkey
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Ankara
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Bournemouth
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Harrow
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Manchester
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Plymouth

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Astellas Pharma Global Development, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Executive Medical Director
Address 0 0
Astellas Pharma Global Development, Inc.
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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.

Supporting document/s available: Study protocol, Statistical analysis plan (SAP), Clinical study report (CSR)
When will data be available (start and end dates)?
Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
Available to whom?
Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: https://www.clinicalstudydatarequest.com/


What supporting documents are/will be available?




Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT02421939