Clinical Trials List
Protocol Number2215-CL-0304
NCT Number(ClinicalTrials.gov Identfier)NCT02997202
2017-03-17 - 2023-04-17
Phase III
Recruiting3
ICD-10C92.A0
Acute myeloid leukemia with multilineage dysplasia, not having achieved remission
A Multi-center, Randomized, Double-blind, Placebo-controlled Phase III Trial of the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/ITD AML
-
Trial Applicant
PAREXEL INTERNATIONAL CO., LTD.
-
Sponsor
Astellas Pharma Global Development, Inc.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Ming-Hung Tsai Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
- Ching Yun Hsieh Division of Hematology & Oncology
- Tzu-Ting Chen Division of Hematology & Oncology
- Li-Yuan Bai Division of Hematology & Oncology
- Che-Hung Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- 洪玉馨 Division of Hematology & Oncology
- Ming-Chung Kao Division of Hematology & Oncology
- Po-Nan Wang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Co-Principal Investigator
- 林建廷 Division of Hematology & Oncology
- Huai-Hsuan Huang Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Wen-Chien Chou Division of Hematology & Oncology
- Chien-Chin Lin Division of Hematology & Oncology
- MING YAO Division of Hematology & Oncology
- Chieh-Lung Cheng Division of Hematology & Oncology
- Chien-Yuan Chen Division of Hematology & Oncology
- Jih-Luh Tang Division of Hematology & Oncology
- Tai-Chung Huang Division of Hematology & Oncology
- CHENG-HONG TSAI Division of Hematology & Oncology
- 田豐銘 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Recruiting
Audit
None
Condition/Disease
Acute Myeloid Leukemia (AML)
Objectives
Primary Objective: The primary objective is to compare relapse-free survival (RFS)
between participants with FLT3/ITD AML in CR1 who undergo HCT
and are randomized to receive gilteritinib or placebo beginning after
the time of engraftment for a two year period.
Secondary Objectives:
1. To determine the safety and tolerability of gilteritinib after HCT.
2. To compare overall survival (OS), non-relapse mortality (NRM)
and event-free survival (EFS) (where events include relapse, death,
stopping therapy and administration of donor lymphocyte infusion
(DLI) or new therapy for suspicion of disease) in participants
treated with gilteritinib as maintenance therapy after HCT
compared to those treated with placebo.
3. To compare 6-month cumulative incidence of grades II-IV and IIIIV acute graft-versus-host disease (GVHD) and 12-month and 24-
month cumulative incidence of mild, moderate, and severe GVHD
in participants treated with gilteritinib as maintenance therapy after
HCT compared to those treated with placebo.
4. To examine the effect of pre- and post-transplant MRD on RFS
and OS
Test Drug
ASP2215
Active Ingredient
Gilteritinib
Dosage Form
Tablet
Dosage
40
Endpoints
Primary Outcome Measures :
Relapse-free survival [ Time Frame: 84 months ]
Relapse-free survival (RFS) will be measured from time of randomization to either leukemia relapse or death, whichever comes first. Leukemia relapse will be defined as bone marrow (BM) blasts 5% or higher (not attributable to regenerating BM), any circulating blasts (not attributable to regenerating BM or growth factors), or any extra-medullary blast foci as per Revised International Working Group (R-IWG) criteria.
Secondary Outcome Measures :
Safety and tolerability assessed by incidence and severity of adverse events [ Time Frame: 24 months ]
All grade ≥ 3 toxicities according to CTCAE (Common Terminology Criteria for Adverse Events) version 4.03 will be tabulated for each treatment arm. The proportion of participants developing grade ≥ 3 AE across treatment arms will be compared. In addition, the incidence of all grade 1 to 4 toxicities according to CTCAE version 4.03 will be tabulated for each treatment arm and compared. Clinical laboratory evaluations and change from baseline will be described and compared. Electrocardiogram (ECG) results and change from baseline will be described and compared. Karnofsky Performance Status scores will be described and compared. The duration of drug use and dose of drug use will also be compared.
Overall Survival (OS) [ Time Frame: 84 months ]
Time to OS is defined as the time to death from any cause after randomization. For surviving participants, non-events will be censored at the last known alive date.
Non-relapse Mortality [ Time Frame: 84 months ]
An event for this endpoint is death without evidence of disease progression or recurrence.
Event-free Survival (EFS) at 12 months [ Time Frame: 12 months ]
The cumulative incidence at 12 months after randomization of EFS will be described and compared.
Event-free Survival (EFS) at 24 months [ Time Frame: 24 months ]
The cumulative incidence at 24 months after randomization of EFS will be described and compared.
Cumulative Incidence of Acute Graft vs. Host Disease (GVHD) [ Time Frame: 6 months ]
The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV acute GVHD will be described and compared. Acute GVHD will be graded according to diagnosis and severity scoring used by the Blood and Marrow Transplant Clinical Trial Network (BMT CTN).
Cumulative Incidence of Chronic GVHD at 12 months [ Time Frame: 12 months ]
The cumulative incidence at 12 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.
Cumulative Incidence of Chronic GVHD at 24 months [ Time Frame: 24 months ]
The cumulative incidence at 24 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.
The cumulative incidence of detection of FLT3/ITD MRD [ Time Frame: 24 months ]
The cumulative incidence of detection of FLT3/ITD MRD in participants who are FLT3/ITD MRD undetectable prior to randomization will be described. Similarly, the pattern of eradication of FLT3/ITD MRD in participants who have detectable FLT3/ITD MRD prior to randomization will be described.
Incidence of Severity of Infection [ Time Frame: 28 months ]
The cumulative incidence of CTCAE grades 3 to 5 infection in participants will be described and compared.
Relapse-free survival [ Time Frame: 84 months ]
Relapse-free survival (RFS) will be measured from time of randomization to either leukemia relapse or death, whichever comes first. Leukemia relapse will be defined as bone marrow (BM) blasts 5% or higher (not attributable to regenerating BM), any circulating blasts (not attributable to regenerating BM or growth factors), or any extra-medullary blast foci as per Revised International Working Group (R-IWG) criteria.
Secondary Outcome Measures :
Safety and tolerability assessed by incidence and severity of adverse events [ Time Frame: 24 months ]
All grade ≥ 3 toxicities according to CTCAE (Common Terminology Criteria for Adverse Events) version 4.03 will be tabulated for each treatment arm. The proportion of participants developing grade ≥ 3 AE across treatment arms will be compared. In addition, the incidence of all grade 1 to 4 toxicities according to CTCAE version 4.03 will be tabulated for each treatment arm and compared. Clinical laboratory evaluations and change from baseline will be described and compared. Electrocardiogram (ECG) results and change from baseline will be described and compared. Karnofsky Performance Status scores will be described and compared. The duration of drug use and dose of drug use will also be compared.
Overall Survival (OS) [ Time Frame: 84 months ]
Time to OS is defined as the time to death from any cause after randomization. For surviving participants, non-events will be censored at the last known alive date.
Non-relapse Mortality [ Time Frame: 84 months ]
An event for this endpoint is death without evidence of disease progression or recurrence.
Event-free Survival (EFS) at 12 months [ Time Frame: 12 months ]
The cumulative incidence at 12 months after randomization of EFS will be described and compared.
Event-free Survival (EFS) at 24 months [ Time Frame: 24 months ]
The cumulative incidence at 24 months after randomization of EFS will be described and compared.
Cumulative Incidence of Acute Graft vs. Host Disease (GVHD) [ Time Frame: 6 months ]
The cumulative incidence at 6 months after randomization of grades II-IV and grades III-IV acute GVHD will be described and compared. Acute GVHD will be graded according to diagnosis and severity scoring used by the Blood and Marrow Transplant Clinical Trial Network (BMT CTN).
Cumulative Incidence of Chronic GVHD at 12 months [ Time Frame: 12 months ]
The cumulative incidence at 12 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.
Cumulative Incidence of Chronic GVHD at 24 months [ Time Frame: 24 months ]
The cumulative incidence at 24 months after randomization of chronic GVHD will be described and compared. Chronic GVHD will be graded according to diagnosis and severity scoring from the NIH 2014 Consensus Criteria.
The cumulative incidence of detection of FLT3/ITD MRD [ Time Frame: 24 months ]
The cumulative incidence of detection of FLT3/ITD MRD in participants who are FLT3/ITD MRD undetectable prior to randomization will be described. Similarly, the pattern of eradication of FLT3/ITD MRD in participants who have detectable FLT3/ITD MRD prior to randomization will be described.
Incidence of Severity of Infection [ Time Frame: 28 months ]
The cumulative incidence of CTCAE grades 3 to 5 infection in participants will be described and compared.
Inclution Criteria
Registration Inclusion Criteria
A participant is eligible for registration to the clinical study if all of the following apply:
1. Participant is considered a suitable candidate for HCT and has an acceptable source of
allogeneic donor stem cells, as defined per institutional practice (allogeneic HCT for any
donor source [matched sibling, unrelated donor (URD), mismatched URD, related
haploidentical, or umbilical cord blood] and any graft source [umbilical cord, BM,
peripheral blood (PB)], and any conditioning [myeloablative conditioning (MAC),
reduced intensity conditioning (RIC), or non-myeloablative conditioning (NMA)] will be
permitted).
2. Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written
informed consent and privacy language as per national regulations (e.g., Health Insurance
Portability and Accountability Act Authorization (HIPAA) for US sites) obtained from
the participant or legally authorized representative prior to any study-related procedures
(including withdrawal of prohibited medication, if applicable).
3. Participant is considered a legal adult by local regulation at the time of signing informed
consent form (ICF).
4. Participant consents to allow access to his or her diagnostic BM aspirate or PB sample
and/or the DNA derived from that sample, if available, that may be used to validate a
companion diagnostic that is being developed in parallel with gilteritinib.
5. Participant has confirmed, morphologically documented AML in CR1. For the purposes
of registration, CR1 will be defined as < 5% blasts in the BM with no morphologic
characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of
extramedullary disease such as central nervous system involvement or granulocytic
sarcoma.
a. Participant has not received more than 2 cycles of induction chemotherapy to achieve
CR1. The induction cycles can be the same regimen or different regimens. The regimen(s) may contain conventional agents, investigational agents, or a combination
of both.
b. Participants with CR with incomplete count recovery (CRp or CRi) are allowed.
Incomplete platelet recovery (CRp) is defined as CR with platelet count < 100 x
109
/L. Incomplete hematologic recovery (CRi) is defined as CR with residual
neutropenia < 1 x 109
/L with or without complete platelet recovery. RBC and platelet
transfusion independence is not required.
c. The maximum time allowed from establishment of CR1 to registration is 12 months.
6. Participant has presence of the FLT3/ITD activating mutation in the BM or PB as
determined by the local institution at diagnosis.
7. Participant must meet the following criteria as indicated on the clinical laboratory tests:
a. Serum creatinine within normal range, or if serum creatinine outside normal range,
then glomerular filtration rate (GFR) > 40 mL/min/1.73m2
as calculated with the
Cockcroft-Gault equation with adjustment if total body weight is ≥ 125% of ideal
body weight.
b. Total bilirubin (TBL) ≤ 2.5 mg/dL, except for participants with Gilbert’s syndrome.
c. Serum AST and/or alanine aminotransferase (ALT) < 3 x institutional upper limit of
normal (ULN).
d. Serum potassium and magnesium greater than the institutional lower limit of normal
(LLN).
8. Participant has left ventricular ejection fraction at rest ≥ 40%.
9. Participant has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for
hemoglobin), forced expiratory volume in 1 second (FEV1), and forced vital capacity
(FVC) > 50% predicted.
10. Female participants must either:
Be of non-childbearing potential:
o postmenopausal (defined as at least 1 year without menses) prior to
screening or
o documented as surgically sterilized (at least 1 month prior to the
screening visit)
Or, if of childbearing potential,
o Agree not to try to become pregnant during the study through 45 days after
the final study drug administration
o And have a negative serum pregnancy test at screening
o 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
45 days after the final study drug administration.
11. Female participants must agree not to breastfeed or donate ova at screening and
throughout the study period and for 45 days after the final study drug administration.
12. Male participants (even if surgically sterilized), and their partners who are women of
childbearing potential must be using highly effective contraception in addition to a barrier method starting at screening and throughout the study period and for 105 days after
the final study drug administration.
13. Male participants must not donate sperm starting at screening and throughout the study
period and for 105 days after the final study drug administration.
14. Participant is able to take an oral medication.
15. Participant agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
A participant is eligible for registration to the clinical study if all of the following apply:
1. Participant is considered a suitable candidate for HCT and has an acceptable source of
allogeneic donor stem cells, as defined per institutional practice (allogeneic HCT for any
donor source [matched sibling, unrelated donor (URD), mismatched URD, related
haploidentical, or umbilical cord blood] and any graft source [umbilical cord, BM,
peripheral blood (PB)], and any conditioning [myeloablative conditioning (MAC),
reduced intensity conditioning (RIC), or non-myeloablative conditioning (NMA)] will be
permitted).
2. Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written
informed consent and privacy language as per national regulations (e.g., Health Insurance
Portability and Accountability Act Authorization (HIPAA) for US sites) obtained from
the participant or legally authorized representative prior to any study-related procedures
(including withdrawal of prohibited medication, if applicable).
3. Participant is considered a legal adult by local regulation at the time of signing informed
consent form (ICF).
4. Participant consents to allow access to his or her diagnostic BM aspirate or PB sample
and/or the DNA derived from that sample, if available, that may be used to validate a
companion diagnostic that is being developed in parallel with gilteritinib.
5. Participant has confirmed, morphologically documented AML in CR1. For the purposes
of registration, CR1 will be defined as < 5% blasts in the BM with no morphologic
characteristics of acute leukemia (e.g., Auer Rods) in the BM with no evidence of
extramedullary disease such as central nervous system involvement or granulocytic
sarcoma.
a. Participant has not received more than 2 cycles of induction chemotherapy to achieve
CR1. The induction cycles can be the same regimen or different regimens. The regimen(s) may contain conventional agents, investigational agents, or a combination
of both.
b. Participants with CR with incomplete count recovery (CRp or CRi) are allowed.
Incomplete platelet recovery (CRp) is defined as CR with platelet count < 100 x
109
/L. Incomplete hematologic recovery (CRi) is defined as CR with residual
neutropenia < 1 x 109
/L with or without complete platelet recovery. RBC and platelet
transfusion independence is not required.
c. The maximum time allowed from establishment of CR1 to registration is 12 months.
6. Participant has presence of the FLT3/ITD activating mutation in the BM or PB as
determined by the local institution at diagnosis.
7. Participant must meet the following criteria as indicated on the clinical laboratory tests:
a. Serum creatinine within normal range, or if serum creatinine outside normal range,
then glomerular filtration rate (GFR) > 40 mL/min/1.73m2
as calculated with the
Cockcroft-Gault equation with adjustment if total body weight is ≥ 125% of ideal
body weight.
b. Total bilirubin (TBL) ≤ 2.5 mg/dL, except for participants with Gilbert’s syndrome.
c. Serum AST and/or alanine aminotransferase (ALT) < 3 x institutional upper limit of
normal (ULN).
d. Serum potassium and magnesium greater than the institutional lower limit of normal
(LLN).
8. Participant has left ventricular ejection fraction at rest ≥ 40%.
9. Participant has diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for
hemoglobin), forced expiratory volume in 1 second (FEV1), and forced vital capacity
(FVC) > 50% predicted.
10. Female participants must either:
Be of non-childbearing potential:
o postmenopausal (defined as at least 1 year without menses) prior to
screening or
o documented as surgically sterilized (at least 1 month prior to the
screening visit)
Or, if of childbearing potential,
o Agree not to try to become pregnant during the study through 45 days after
the final study drug administration
o And have a negative serum pregnancy test at screening
o 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
45 days after the final study drug administration.
11. Female participants must agree not to breastfeed or donate ova at screening and
throughout the study period and for 45 days after the final study drug administration.
12. Male participants (even if surgically sterilized), and their partners who are women of
childbearing potential must be using highly effective contraception in addition to a barrier method starting at screening and throughout the study period and for 105 days after
the final study drug administration.
13. Male participants must not donate sperm starting at screening and throughout the study
period and for 105 days after the final study drug administration.
14. Participant is able to take an oral medication.
15. Participant agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
Exclusion Criteria
Registration Exclusion Criteria
A participant will be excluded from participation in this clinical study if any of the following
apply:
1. Participant has had a prior allogeneic transplant.
2. Participant has Karnofsky performance status score < 70% (APPENDIX F).
3. Participant requires treatment with concomitant drugs that are strong inducers of
CYP3A4.
4. 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 participant.
5. Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of
triplicate determinations).
6. Participant has long QT Syndrome at screening.
7. Participant has a known infection with human immunodeficiency virus (HIV) as
determined by serology or nucleic acid amplification test (NAAT).
8. Participant has active hepatitis B infection as determined by NAAT or surface antigen
assay. Participants who have acquired immunity from past exposure (HBcAb positive /
HBsAb positive / HBsAg negative) are eligible.
9. Participant has active hepatitis C infection as determined by NAAT. Participants who
have had past exposure and have no detectable virus either through spontaneous
clearance or treatment are eligible.
10. Participant with uncontrolled infections will be excluded. If a bacterial or viral infection
is present, the participant must be receiving definitive therapy and have no signs of
progressing infection for 72 hours prior to registration. If a fungal infection is present, the
participant must be receiving definitive systemic anti-fungal therapy and have no signs of
progressing infection for 1 week prior to registration.
Progressing infection is defined as hemodynamic instability attributable to sepsis or
new symptoms, worsening physical signs or radiographic findings attributable to
infection.
Persisting fever without other signs or symptoms will not be interpreted as
progressing infection.
11. Participant has had a myocardial infarction within 6 months prior to registration or New
York Heart Association (NYHA) Class III or IV heart failure (APPENDIX D),
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic
evidence of acute ischemia.
12. Participant has a serious medical or psychiatric illness likely to interfere with
participation in this clinical study.
13. Female participants who are breast feeding or pregnant.
14. Participant has prior malignancies, except lobular breast carcinoma in situ, fully resected
basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ.
Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated
with curative intent < 5 years previously will not be allowed.
Waivers to the exclusion criteria will NOT be allowed.
A participant will be excluded from participation in this clinical study if any of the following
apply:
1. Participant has had a prior allogeneic transplant.
2. Participant has Karnofsky performance status score < 70% (APPENDIX F).
3. Participant requires treatment with concomitant drugs that are strong inducers of
CYP3A4.
4. 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 participant.
5. Participant has a Fridericia-corrected QT interval (QTcF) > 450 msec (average of
triplicate determinations).
6. Participant has long QT Syndrome at screening.
7. Participant has a known infection with human immunodeficiency virus (HIV) as
determined by serology or nucleic acid amplification test (NAAT).
8. Participant has active hepatitis B infection as determined by NAAT or surface antigen
assay. Participants who have acquired immunity from past exposure (HBcAb positive /
HBsAb positive / HBsAg negative) are eligible.
9. Participant has active hepatitis C infection as determined by NAAT. Participants who
have had past exposure and have no detectable virus either through spontaneous
clearance or treatment are eligible.
10. Participant with uncontrolled infections will be excluded. If a bacterial or viral infection
is present, the participant must be receiving definitive therapy and have no signs of
progressing infection for 72 hours prior to registration. If a fungal infection is present, the
participant must be receiving definitive systemic anti-fungal therapy and have no signs of
progressing infection for 1 week prior to registration.
Progressing infection is defined as hemodynamic instability attributable to sepsis or
new symptoms, worsening physical signs or radiographic findings attributable to
infection.
Persisting fever without other signs or symptoms will not be interpreted as
progressing infection.
11. Participant has had a myocardial infarction within 6 months prior to registration or New
York Heart Association (NYHA) Class III or IV heart failure (APPENDIX D),
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic
evidence of acute ischemia.
12. Participant has a serious medical or psychiatric illness likely to interfere with
participation in this clinical study.
13. Female participants who are breast feeding or pregnant.
14. Participant has prior malignancies, except lobular breast carcinoma in situ, fully resected
basal cell or squamous cell carcinoma of skin or treated cervical carcinoma in situ.
Cancer treated with curative intent > 5 years previously will be allowed. Cancer treated
with curative intent < 5 years previously will not be allowed.
Waivers to the exclusion criteria will NOT be allowed.
The Estimated Number of Participants
-
Taiwan
12 participants
-
Global
1000 participants
