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Protocol NumberAG120-C-009
NCT Number(ClinicalTrials.gov Identfier)NCT03173248

2017-07-18 - 2024-06-30

Phase III

Recruiting6

ICD-10C92.A0

Acute myeloid leukemia with multilineage dysplasia, not having achieved remission

A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination with Azacitidine in Subjects 18 Years of Age with previously Untreated Acute Myeloid Leukemia with an IDH1 Mutation

  • Trial Applicant

    PPD DEVELOPMENT (HK) LIMITED

  • Sponsor

    Agios Pharmaceuticals, Inc.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2025/08/20

Investigators and Locations

Principal Investigator Su-Peng Yeh Division of Hematology & Oncology
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 王銘崇 Division of Hematology & Oncology
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 蕭聖諺 Division of Hematology & Oncology
Chi Mei Hospital, Liouying

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator 賴冠銘 Division of Hematology & Oncology
CHANGHUA CHRISTIAN HOSPITAL

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Principal Investigator Su-Peng Yeh 未分科
China Medical University Hospital-Taipei

Co-Principal Investigator

Audit

None

Principal Investigator Hui-Hua Hsiao 未分科
Kaohsiung Municipal Gangshan Hospital

Co-Principal Investigator

Audit

None

Principal Investigator HSIN-AN HOU Division of Hematology & Oncology
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Audit

None

Principal Investigator Hui-Hua Hsiao Division of Hematology & Oncology
Kaohsiung Medical Univeristy Chung-Ho Memorial Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Acute Myeloid Leukemia with an IDH1 Mutation

Objectives

Primary Objective: • To determine if treatment with AG-120 in combination with azacitidine significantly prolongs overall survival (OS) compared with placebo administered with azacitidine in subjects with previously untreated isocitrate dehydrogenase 1 mutation-positive (IDH1m) acute myeloid leukemia (AML).

Test Drug

Ivosidenib (AG-120);Azacitidine

Active Ingredient

Azacitidine
Ivosidenib (AG-120)

Dosage Form

oral tablet
injection

Dosage

250
100

Endpoints

Primary Outcome Measures :
Event-Free Survival (EFS) [ Time Frame: Up to approximately 52 months ]
EFS is defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.


Secondary Outcome Measures :
Complete Remission Rate (CR Rate) [ Time Frame: Up to approximately 52 months ]
CR rate is defined as the proportion of participants who achieve a CR. A Cochran-Mantel-Haenszel (CMH) test will be used to compare CR rate between the 2 treatment arms.

Overall Survival (OS) [ Time Frame: Up to approximately 52 months ]
OS is defined as the time from date of randomization to the date of death due to any cause. Kaplan-Meier (KM) curves and KM estimates of OS will be presented for each treatment arm.

CR + Complete Remission With Partial Hematologic (CRh) Rate [ Time Frame: Up to approximately 52 months ]
CR + CRh rate is defined as the proportion of participants who achieve a CR or CRh. CRh is defined as a CR with partial recovery of peripheral blood counts (less than 5% bone marrow blasts, absolute neutrophil count (ANC) greater than 0.5 × 10^9/liter (L) 500/microliter (μL)], and platelets greater than 50 × 10^9/L [50,000/μL]). A CMH test will be used to compare the CR + CRh rate between the 2 treatment arms.

Objective Response Rate (ORR) [ Time Frame: Up to approximately 52 months ]
ORR is defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS). The best response is calculated using the following hierarchy: CR, followed by CRi (including CRp), followed by PR and MLFS. A summary of best response by treatment arm will be produced. A CMH test will be used to compare ORR between the 2 treatment arms.

CR + CRi (Including CRp) Rate [ Time Frame: Up to approximately 52 months ]
The CR + CRi (including CRp) rate is defined as the proportion of participants who achieve a CR or CRi (including CRp). A CMH test will be used to compare the CR + CRi (including CRp) rate between the 2 treatment arms.

Duration of CR (DOCR) [ Time Frame: Up to approximately 52 months ]
DOCR will be calculated as the date of the first occurrence of CR to the date of first documented disease relapse, or death. DOCR is only defined for participants who achieve a CR.

Duration of CRh (DOCRh) [ Time Frame: Up to approximately 52 months ]
DOCRh will be calculated as the date of the first occurrence of CR or CRh to the date of first documented disease relapse or death. DOCRh is only defined for participants who achieve a CR or CRh.

Duration of Response (DOR) [ Time Frame: Up to approximately 52 months ]
DOR will be calculated as the date of the first response to the date of first documented disease relapse, disease progression, or death. DOR is only defined for participants who achieve a CR, CRi (including CRp), PR, and/or MLFS.

Duration of CRi (DOCRi) [ Time Frame: Up to approximately 52 months ]
DOCRi will be calculated as the date of the first occurrence of CR or CRi (including CRp) to the date of the first documented relapse or death. DOCRi is only defined for participants who achieve a CR or CRi (including CRp).

Time to CR (TTCR) [ Time Frame: Up to approximately 52 months ]
TTCR will be assessed from the date of randomization to the date of first occurrence of CR. TTCR is only defined for participants who achieve a CR.

Time to CRh (TTCRh) [ Time Frame: Up to approximately 52 months ]
TTCRh will be assessed from the date of randomization to the date of first occurrence of CR or CRh. TTCRh is only defined for participants who achieve a CR or CRh.

Time to Response (TTR) [ Time Frame: Up to approximately 52 months ]
TTR will be assessed from the date of randomization to the date of the first response. TTR is only defined for participants who achieve a CR, CRi (including CRp), PR, and/or MLFS.

Time to CRi (TTCRi) [ Time Frame: Up to approximately 52 months ]
TTCRi will be assessed from the date of randomization to the date of first occurrence of CR or CRi (including CRp). TTCRi is only defined for participants who achieve a CR or CRi (including CRp).

Percentage of Participants with Abnormalities in Vital Sign Measurements [ Time Frame: From Baseline up to approximately 1 week after last dose of treatment (up to a maximum of 52 months) ]
Vital signs will include body temperature, respiratory rate, blood pressure, and heart rate.

Percentage of Participants with Abnormalities in Eastern Cooperative Oncology Group Performance Status (ECOG PS) [ Time Frame: From Baseline up to approximately 1 week after last dose of treatment (up to a maximum of 52 months) ]
Percentage of Participants with Abnormalities in 12-lead Electrocardiograms (ECGs) [ Time Frame: From Baseline up to approximately 1 week after last dose of treatment (up to a maximum of 52 months) ]
Percentage of Participants with Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF) [ Time Frame: From Baseline up to approximately 1 week after last dose of treatment (up to a maximum of 52 months) ]
LVEF is determined by ECHO or MUGA scan in participants.

Percentage of Participants with Abnormalities in Clinical Laboratory Tests [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
Clinical laboratory assessments will include hematology, serum chemistry, coagulation.

Percentage of Participants with Adverse Events (AEs) [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a investigational medicinal product; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug.

Percentage of Participants with AEs of Special Interest (AESIs) [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
AESIs are AEs that are not solicited local or systemic AEs, they are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESIs include protocol-specified QT prolongation, isocitrate dehydrogenase (IDH) differentiation syndrome and leukocytosis.

Percentage of Participants with Serious Adverse Events (SAEs) [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
An SAE is defined as an untoward medical occurrence, significant hazard, contraindication, side effect or precaution that at any dose: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.

Percentage of Participants Using Concomitant Medications [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (ie, potassium and magnesium).

Units of Platelets and Red Blood Cells (RBC) Infused [ Time Frame: Up to approximately 52 months ]
All measures that are indicative of clinical benefit are measured like number of units of platelet and RBC infused.

Rate of Infection [ Time Frame: Up to approximately 52 months ]
Days Spent Hospitalized [ Time Frame: Up to approximately 52 months ]
Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLC-C30 Questionnaire [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
The EORTC QLQ-C30 questionnaire measures quality of life and consists of 30 questions that are incorporated into 5 functional domains (physical, role, cognitive, emotional, and social); a global health status/global quality of life; 3 symptom scales (fatigue, pain, and nausea and vomiting); and 6 single items that assess additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and the perceived financial burden of treatment experienced by participants with cancer.

Change From Baseline in the EORTC EQ-5D-5L Questionnaire [ Time Frame: From Baseline up to approximately 4 weeks after last dose of treatment (up to a maximum of 52 months) ]
The EORTC EQ-5D-5L questionnaire measures quality of life and spans 5 dimensions, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, which are used to build a composite of the participant's health status.

Percentage of Participants With CR With IDH1 Mutation Clearance (MC) [ Time Frame: Up to approximately 52 months ]
CR with IDH1 MC is defined as a response of CR where there is no evidence of the IDH1 mutation by molecular techniques to below the level of detection (0.02%-0.04%) for ≥1 on-treatment time point. A CMH test will be used to compare the rate of CR between 2 treatment arms.

Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities [ Time Frame: From Baseline up to the last dose of treatment (up to a maximum of 52 months) ]
The number of doses administered, total dose, duration of treatment, dose intensity, and the proportion of participants with dose modifications, will be summarized by treatment arm.

Circulating Plasma Concentration of AG-120 and 2-HG [ Time Frame: From Baseline up to the last dose of treatment (up to a maximum of 52 months) ]
Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.

Inclution Criteria

Inclusion Criteria:
Subjects must meet all of the following criteria to be eligible for inclusion in the study:
1. Be ≥ 18 years of age.
2. Have previously untreated AML, defined according to World Health Organization (WHO)
criteria, with ≥ 20% leukemic blasts in the bone marrow. Subjects with extramedullary disease
alone (ie, no detectable bone marrow and no detectable peripheral blood AML) are not eligible
for the study.
3. Have an IDH1 mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution,
as determined by central laboratory testing (using an investigational polymerase chain reaction
[PCR] assay, Abbott RealTime IDH1) in their bone marrow aspirate and/or peripheral blood sample.
(Note: Local testing for eligibility and randomization is permitted with medical monitor
approval; however, results must state an IDH1 mutation resulting in an R132C, R132G,
R132H, R132L, or R132S substitution. Peripheral blood and bone marrow aspirate samples for
central testing must have been received at the central laboratory prior to randomization.)
4. Have an ECOG PS score of 0 to 2.
5. Have adequate hepatic function, as evidenced by:
a. Serum total bilirubin ≤ 1.5 times the upper limit of normal (× ULN), unless considered to
be due to Gilbert’s disease or underlying leukemia, where it must be < 3 × ULN.
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) ≤ 3.0 × ULN, unless considered to be due to underlying leukemia.
6. Have adequate renal function, as evidenced by serum creatinine ≤ 2.0 × ULN or creatinine
clearance > 40 mL/min based on the Cockcroft-Gault glomerular filtration rate.
7. Have agreed to undergo serial blood and bone marrow sampling.
8. Be able to understand and willing to sign an informed consent form (ICF).
9. Be willing to complete QoL assessments during study treatment and at the designated time
points following treatment discontinuation.
10. If female with reproductive potential, must have a negative serum pregnancy test prior to the
start of study therapy. Female subjects with reproductive potential are defined as sexually
mature women who have not undergone a hysterectomy, bilateral oophorectomy, or tubal
occlusion or who have not been naturally postmenopausal for at least 24 consecutive months.
Females of reproductive potential, as well as fertile men and their female partners of
reproductive potential, must agree to use 2 effective forms of contraception (including at least
1 barrier form) from the time of giving informed consent throughout the study and for 90 days
(both females and males) following the last dose of study drug(s). Effective forms of
contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine
devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with
spermicide, or male partner sterilization.

Exclusion Criteria

Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from the study:
1. Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML.
2. Have received any prior treatment for AML with the exception of nononcolytic treatments to
stabilize disease such as hydroxyurea or leukapheresis.
3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).
4. Subjects who had previously received an experimental agent for MDS may not be randomized
until a washout period of at least 5 half-lives of the experimental agent has elapsed since the
last dose of that agent.
5. Have received prior treatment with an IDH1 inhibitor.
6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.
7. Are female and pregnant or breastfeeding.
8. Are taking known strong cytochrome P450 (CYP) 3A4 inducers or sensitive CYP3A4
substrate medications with a narrow therapeutic window, unless they can be transferred to
other medications within ≥ 5 half-lives prior to dosing.
9. Are taking P-glycoprotein (P-gp) transporter-sensitive substrate medications with a narrow
therapeutic window, unless they can be transferred to other medications within ≥ 5 half-lives
prior to administration of study treatment.
10. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without
improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
11. Have a prior history of malignancy other than MDS or myeloproliferative disorder, 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 or similar indolent cancer are allowed
to participate in the study:
a. Basal or squamous cell carcinoma of the skin
b. Carcinoma in situ of the cervix
c. Carcinoma in situ of the breast
d. Incidental histologic finding of prostate cancer
12. Have had significant active cardiac disease within 6 months prior to the start of study
treatment, including New York Heart Association Class III or IV congestive heart failure,
myocardial infarction, unstable angina, and/or stroke.
13. Have a heart-rate corrected QT interval using Fridericia’s method (QTcF) ≥ 470 msec or any
other factor that increases the risk of QT prolongation or arrhythmic events (eg, heart failure,
hypokalemia, family history of long QT interval syndrome). Subjects with prolonged QTcF
interval in the setting of bundle branch block may participate in the study.
14. Have an active viral infection caused by human immunodeficiency virus, hepatitis B virus, or
hepatitis C virus that cannot be controlled by treatment.
15. Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the
ingestion or gastrointestinal absorption of orally administered drugs.
16. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).
17. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known
CNS leukemia. Evaluation of cerebrospinal fluid during Screening is only required if there is a
clinical suspicion of CNS involvement by leukemia during Screening.
18. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled
bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
19. Have any other medical or psychological condition deemed by the Investigator to be likely to
interfere with the subject’s ability to give informed consent or participate in the study.
20. Are taking medications that are known to prolong the QT interval (Appendix 15.5) unless they
can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the
medications can be properly monitored during the study. (If equivalent medication is not
available, heart rate corrected Qt interval (QTc) will be closely monitored as defined in Section 9.12.2).

The Estimated Number of Participants

  • Taiwan

    12 participants

  • Global

    392 participants

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