Clinical Trials List
Protocol NumberAG-221-AML-004
NCT Number(ClinicalTrials.gov Identfier)NCT02577406
2016-06-01 - 2001-06-01
Phase III
Terminated3
ICD-10C92.A0
Acute myeloid leukemia with multilineage dysplasia, not having achieved remission
A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects with Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
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Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
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Sponsor
Celgene Corporation
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Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Ching Yun Hsieh Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
- Li-Yuan Bai Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
- Che-Hung Lin Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- 高小雯 Division of Hematology & Oncology
- 歐哲瑋 Division of Hematology & Oncology
- Tung-Liang Lin Division of Hematology & Oncology
- Po-Nan Wang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Co-Principal Investigator
- 劉家豪 Division of Hematology & Oncology
- Tai-Chung Huang Division of Hematology & Oncology
- Huai-Hsuan Huang Division of Hematology & Oncology
- Chieh-Lung Cheng Division of Hematology & Oncology
- Chien-Yuan Chen Division of Hematology & Oncology
- Chien-Chin Lin Division of Hematology & Oncology
- Wen-Chien Chou Division of Hematology & Oncology
- CHENG-HONG TSAI Division of Hematology & Oncology
- Shang-Ju Wu Division of Hematology & Oncology
- Jih-Luh Tang Division of Hematology & Oncology
- HSIN-AN HOU Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Audit
None
Condition/Disease
Acute Myeloid Leukemia
Objectives
Primary
To determine the primary efficacy, measured as overall survival (OS), of AG-221
compared with conventional care regimens (CCRs) in subjects 60 years or older with
AML refractory to or relapsed after second- or third-line AML therapy and positive
for an IDH2 mutation
Secondary
To determine the supporting efficacy of AG-221 compared with CCRs
To determine the safety and tolerability of AG-221 compared with CCRs
To determine the effect of AG-221 compared with CCRs on Health-related Qualityof-Life (HRQoL)
Test Drug
AG-221 (CC-90007)
Active Ingredient
AG-221 (CC-90007)
Dosage Form
oral tablet
Dosage
50 mg,100mg,150mg,200mg
Endpoints
Overview of Key Efficacy Assessments
The primary efficacy endpoint is OS.
The key secondary efficacy endpoints include overall response rate and event-free survival.
Response will be assessed retrospectively by a blinded IRAC through collection of central
hematology parameters, central assessments of bone marrow aspirates and/or biopsies, peripheral
blood smears and cytogenetics, and results of other pertinent tests.
Overview of Key Safety Assessments
Safety assessments include physical examination, vital signs, electrocardiogram, hematology,
serum chemistry, cardiac markers, fasting lipid panel, pregnancy testing (for females of
childbearing potential only), AEs, concomitant medications, concomitant procedures and
transfusions. After screening, echocardiogram or multi-gated acquisition scan, urinalysis and
coagulation will be repeated as clinically indicated.
The primary efficacy endpoint is OS.
The key secondary efficacy endpoints include overall response rate and event-free survival.
Response will be assessed retrospectively by a blinded IRAC through collection of central
hematology parameters, central assessments of bone marrow aspirates and/or biopsies, peripheral
blood smears and cytogenetics, and results of other pertinent tests.
Overview of Key Safety Assessments
Safety assessments include physical examination, vital signs, electrocardiogram, hematology,
serum chemistry, cardiac markers, fasting lipid panel, pregnancy testing (for females of
childbearing potential only), AEs, concomitant medications, concomitant procedures and
transfusions. After screening, echocardiogram or multi-gated acquisition scan, urinalysis and
coagulation will be repeated as clinically indicated.
Inclution Criteria
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 60 years of age at the time of signing the ICF
2. Subject has primary (ie, de novo) or secondary (progression of MDS or
myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO
classification (Appendix B)
3. Subject has received second- or third-line/regimen of AML therapy (see Appendix G for
the definition of prior AML line/regimen)
4. Subject has the following disease status:
a. Refractory to or relapsed after second- or third-line/regimen of intensive therapy
for AML (eg, the “7 + 3” regimen):
at least 5% leukemic blasts in bone marrow; or
b. Refractory to or relapsed after second- or third-line low-intensity AML therapy
(eg, LDAC, azacitidine or decitabine):
at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles
5. Subject is eligible for and willing to receive the pre-selected CCR treatment option,
according to the investigator's assessment
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
2 (Appendix D)
7. Subject has IDH2 gene mutations tested centrally (using the “investigational use only”
PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral
blood, and confirmed positive in bone marrow aspirate and/or peripheral blood
8. Subject has adequate organ function defined as:
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
≤ 3 x upper limit of normal (ULN), unless considered due to leukemic organ
involvement, following review by the Medical Monitor; and
Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert’s syndrome (eg, a
gene mutation in UGT1A1) or leukemic organ involvement, following review by the
Medical Monitor; and
Creatinine clearance 30 mL/min based on the Cockcroft-Gault glomerular filtration
rate estimation: (140Age)(weight in kg)(0.85 if female)/72serum creatinine
9. Females of childbearing potential (FCBP)* may participate, providing they meet the
following conditions:
Agree to abstain from sexual intercourse or to use at least two effective contraceptive
methods (oral, injectable, patch, or implantable hormonal contraceptive; tubal
ligation; intra-uterine device; synthetic double-barrier contraceptive with spermicide;
or vasectomized partner) at screening and throughout the study, and for 4 months
following the last study treatment; and
Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG)
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
Have a negative serum or urine (investigator’s discretion under local regulations)
β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the
start of study treatment in the Treatment Phase (note that the screening serum
pregnancy test can be used as the test prior to the start of study treatment in the
Treatment Phase if it is performed within the 72-hour timeframe).
10. Male subjects with a female partner of childbearing potential must agree to abstain from
sexual intercourse or to the use of at least two effective contraceptive methods
(eg, synthetic condoms with spermicide, etc) at screening and throughout the course of
the study and should avoid fathering a child during the course of the study and for
4 months following the last study treatment (6 months following the last dose of
azacitidine in Canada)
11. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted
12. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 60 years of age at the time of signing the ICF
2. Subject has primary (ie, de novo) or secondary (progression of MDS or
myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO
classification (Appendix B)
3. Subject has received second- or third-line/regimen of AML therapy (see Appendix G for
the definition of prior AML line/regimen)
4. Subject has the following disease status:
a. Refractory to or relapsed after second- or third-line/regimen of intensive therapy
for AML (eg, the “7 + 3” regimen):
at least 5% leukemic blasts in bone marrow; or
b. Refractory to or relapsed after second- or third-line low-intensity AML therapy
(eg, LDAC, azacitidine or decitabine):
at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles
5. Subject is eligible for and willing to receive the pre-selected CCR treatment option,
according to the investigator's assessment
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or
2 (Appendix D)
7. Subject has IDH2 gene mutations tested centrally (using the “investigational use only”
PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral
blood, and confirmed positive in bone marrow aspirate and/or peripheral blood
8. Subject has adequate organ function defined as:
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
≤ 3 x upper limit of normal (ULN), unless considered due to leukemic organ
involvement, following review by the Medical Monitor; and
Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert’s syndrome (eg, a
gene mutation in UGT1A1) or leukemic organ involvement, following review by the
Medical Monitor; and
Creatinine clearance 30 mL/min based on the Cockcroft-Gault glomerular filtration
rate estimation: (140Age)(weight in kg)(0.85 if female)/72serum creatinine
9. Females of childbearing potential (FCBP)* may participate, providing they meet the
following conditions:
Agree to abstain from sexual intercourse or to use at least two effective contraceptive
methods (oral, injectable, patch, or implantable hormonal contraceptive; tubal
ligation; intra-uterine device; synthetic double-barrier contraceptive with spermicide;
or vasectomized partner) at screening and throughout the study, and for 4 months
following the last study treatment; and
Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG)
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
Have a negative serum or urine (investigator’s discretion under local regulations)
β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the
start of study treatment in the Treatment Phase (note that the screening serum
pregnancy test can be used as the test prior to the start of study treatment in the
Treatment Phase if it is performed within the 72-hour timeframe).
10. Male subjects with a female partner of childbearing potential must agree to abstain from
sexual intercourse or to the use of at least two effective contraceptive methods
(eg, synthetic condoms with spermicide, etc) at screening and throughout the course of
the study and should avoid fathering a child during the course of the study and for
4 months following the last study treatment (6 months following the last dose of
azacitidine in Canada)
11. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted
12. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements
Exclusion Criteria
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype (Appendix B)
2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C)
3. Subject has received a targeted agent against an IDH2 mutation
4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the
start of study treatment. Note that hydroxyurea is allowed prior to the start of study
treatment for the control of leukocytosis in subjects with white blood cell (WBC) counts
> 30 x 109
/L (however, hydroxyurea should not be given within 72 hours prior to and
after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives,
whichever is longer, prior to the start of study treatment
6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on
immunosuppressive therapy post HSCT at the time of screening, or with clinically
significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid
post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior
therapies
8. Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment)
10. Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation
11. Subject has significant active cardiac disease within 6 months prior to the start of study
treatment, including New York Heart Association (NYHA) class III or IV congestive
heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment
12. Subject has prior history of malignancy, other than MDS, MPN or AML, unless the
subject has been free of the disease for ≥ 1 year prior to the start of study treatment.
However, subjects with the following history/concurrent conditions are allowed:
Basal or squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node,
metastasis clinical staging system)
13. Subject is known seropositive or active infection with human immunodeficiency virus
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs administered
orally
15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 100 mmHg)
16. Subject is a pregnant or lactating female
17. Subject has known or suspected to have hypersensitivity to any of the components of
study treatment
18. Subject is taking those medications (listed in Section 8.2) that are known to prolong QT
interval
19. Subject has QTc interval (ie, Fridericia’s correction [QTcF]) ≥ 450 ms or other factors
that increase the risk of QT prolongation or arrhythmic events (eg, heart failure,
hypokalemia, family history of long QT interval syndrome) at screening
20. Subject is taking the following sensitive CYP substrate medications that have a narrow
therapeutic range are excluded from the study unless the subject can be transferred to
other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and
docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine
(CYP2D6), theophylline, and tizanidine (CYP1A2)
21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
substrate rosuvastatin should be excluded from the study unless the subject can be
transferred to other medications at least 5 half-lives prior to the start of study treatment
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study
The presence of any of the following will exclude a subject from enrollment:
1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype (Appendix B)
2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C)
3. Subject has received a targeted agent against an IDH2 mutation
4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the
start of study treatment. Note that hydroxyurea is allowed prior to the start of study
treatment for the control of leukocytosis in subjects with white blood cell (WBC) counts
> 30 x 109
/L (however, hydroxyurea should not be given within 72 hours prior to and
after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives,
whichever is longer, prior to the start of study treatment
6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on
immunosuppressive therapy post HSCT at the time of screening, or with clinically
significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid
post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior
therapies
8. Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as
ongoing signs/symptoms related to the infection without improvement despite
appropriate antibiotics, antiviral therapy, and/or other treatment)
10. Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation
11. Subject has significant active cardiac disease within 6 months prior to the start of study
treatment, including New York Heart Association (NYHA) class III or IV congestive
heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment
12. Subject has prior history of malignancy, other than MDS, MPN or AML, unless the
subject has been free of the disease for ≥ 1 year prior to the start of study treatment.
However, subjects with the following history/concurrent conditions are allowed:
Basal or squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node,
metastasis clinical staging system)
13. Subject is known seropositive or active infection with human immunodeficiency virus
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs administered
orally
15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 100 mmHg)
16. Subject is a pregnant or lactating female
17. Subject has known or suspected to have hypersensitivity to any of the components of
study treatment
18. Subject is taking those medications (listed in Section 8.2) that are known to prolong QT
interval
19. Subject has QTc interval (ie, Fridericia’s correction [QTcF]) ≥ 450 ms or other factors
that increase the risk of QT prolongation or arrhythmic events (eg, heart failure,
hypokalemia, family history of long QT interval syndrome) at screening
20. Subject is taking the following sensitive CYP substrate medications that have a narrow
therapeutic range are excluded from the study unless the subject can be transferred to
other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and
docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine
(CYP2D6), theophylline, and tizanidine (CYP1A2)
21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
substrate rosuvastatin should be excluded from the study unless the subject can be
transferred to other medications at least 5 half-lives prior to the start of study treatment
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study
The Estimated Number of Participants
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Taiwan
15 participants
-
Global
316 participants
