Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation

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

Status

Active, not recruiting

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03173248

Acronym

AGILE

Enrollment

146

Registered

2017-06-01

Start date

2017-06-26

Completion date

2026-06-30

Last updated

2025-11-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Newly Diagnosed Acute Myeloid Leukemia (AML), Untreated AML, AML Arising From Myelodysplastic Syndrome (MDS), Leukemia, Myeloid, Acute

Keywords

Acute Myeloid Leukemia, Leukemia, Azacitidine, AG-120, ivosidenib

Brief summary

Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of AG-120 (ivosidenib) + azacitidine vs placebo + azacitidine in adult participants with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy. The primary endpoint is event-free survival (EFS). The key secondary efficacy endpoints are overall survival (OS), rate of complete remission (CR), rate of CR and complete remission with partial hematologic recovery (CRh), and overall response rate (ORR). Participants eligible for study treatment based on Screening assessments will be randomized 1:1 to receive oral AG-120 or matched placebo, both administered in combination with subcutaneous (SC) or intravenous (IV) azacitidine. An estimated 200 participants will take part in the study.

Interventions

DRUGAG-120

Tablets administered orally

DRUGPlacebo

Tablets administered orally

DRUGAzacitidine

Administered SC or IV

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Be ≥ 18 years of age and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC): ≥ 75 years old, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2, severe cardiac disorder (e.g., congestive heart failure requiring treatment, left ventricular ejection fraction (LVEF), ≤50%, or chronic stable angina), severe pulmonary disorder (e.g., diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%), creatinine clearance \<45 mL/minute, bilirubin \>1.5 times the upper limit of normal (ULN) and/or have any other comorbidity that the Investigator judges to be incompatible with intensive IC and must be reviewed and approved by the Medical Monitor before study enrollment. 2. Have previously untreated AML, defined according to World Health Organization (WHO) criteria, with ≥ 20% leukemic blasts in the bone marrow. Participants with extramedullary disease alone (i.e., no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study. 3. Have an isocitrate dehydrogenase 1 (IDH1) mutation. 4. Have an ECOG PS score of 0 to 2. 5. Have adequate hepatic function. 6. Have adequate renal function. 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 Quality of Life assessments during the study 10. If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. 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.

Exclusion criteria

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 hydroxyurea. 3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS). 4. Participants who had previously received an experimental agent for MDS may not be randomized until a washout period 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. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment. 9. Have a prior history of cancer other than MDS or myeloproliferative disorder, unless the participant has been free of the disease for ≥ 1 year prior to the start of study treatment. 10. Have had significant active cardiac disease within 6 months prior to the start of the study treatment. 11. Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia. 12. Have a condition that limits the ingestion or absorption of drugs administered by mouth. 13. Have uncontrolled hypertension (systolic blood pressure \[BP\] \> 180 mmHg or diastolic BP \> 100 mmHg). 14. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. 15. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation. 16. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the participant's ability to give informed consent or participate in the study. 17. Are taking medications that are known to prolong the QT interval 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.) 18. Have a known medical history of progressive multifocal leukoencephalopathy.

Design outcomes

Primary

Measure	Time frame	Description
Event-Free Survival (EFS)	Up to Week 24	EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure was defined as failure to achieve complete remission (CR) by Week 24. CR: Bone marrow blasts \<5% and no Auer rods; absence of extramedullary disease; Absolute neutrophil count (ANC) ≥1.0 × 10\^9 per litre (10\^9/L) (1000 per microlitre \[1000/μL\]); platelet count ≥100 × 10\^9/L (100,000/μL); independence of red blood cell transfusions. Participants who had an EFS event (relapse or death) after, 2 or more missing disease assessments were censored at the last adequate disease assessment documenting no relapse before the missing assessments. The reported data represents the Kaplan-Meier median value.

Secondary

Measure	Time frame	Description
Overall Survival (OS)	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	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)	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	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)	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)	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)	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)	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)	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)	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)	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)	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	Up to approximately 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)	Up to approximately 52 months	—
Percentage of Participants With Abnormalities in 12-lead Electrocardiograms (ECGs)	Up to approximately 52 months	—
Complete Remission Rate (CR Rate)	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.
Percentage of Participants With Abnormalities in Clinical Laboratory Tests	Up to approximately 52 months	Clinical laboratory assessments will include hematology, serum chemistry, coagulation.
Percentage of Participants With Adverse Events (AEs)	Up to approximately 52 months	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered an 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)	Up to approximately 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)	Up to approximately 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 With Adverse Events Leading to Discontinuation or Death	Up to approximately 52 months	An AE is defined as any untoward medical occurrence in a clinical investigation participant administered an 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 Using Concomitant Medications	Up to approximately 52 months	Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (i.e., potassium and magnesium).
Units of Platelets and Red Blood Cells (RBC) Infused	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	Up to approximately 52 months	—
Number of Days Spent Hospitalized	Up to approximately 52 months	—
Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) QLC-C30 Questionnaire	Up to approximately 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	Up to approximately 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)	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	Up to approximately 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	Up to approximately 52 months	Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.
Circulating Plasma Concentration of 2-HG	Up to approximately 52 months	Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.
Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF)	Up to approximately 52 months	LVEF is determined by ECHO or MUGA scan in participants.

Countries

Australia, Austria, Brazil, Canada, China, Czechia, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Russia, South Korea, Spain, Taiwan, United Kingdom, United States

Participant flow

Recruitment details

Participants took part in the study at 199 investigational sites from 19 March 2018 to 18 March 2021 (data cut off date). This study is ongoing. Results collected through data cut off date, 18 March 2021 are being reported.

Pre-assignment details

A total of 146 participants with previously untreated isocitrate dehydrogenase 1 mutation-positive (IDH1m) acute myeloid leukemia (AML) were randomized into a 1:1 ratio to receive ivosidenib (AG-120) or AG-120 matched placebo in combination with azacitidine.

Participants by arm

Arm	Count
AG-120 + Azacitidine Participants received AG-120 500 mg orally, QD in combination with azacitidine 75 mg/m\^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.	72
Placebo + Azacitidine Participants received AG-120 matching placebo orally, QD in combination with azacitidine 75 mg/m\^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.	74
Total	146

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	28	46
Overall Study	Lost to Follow-up	0	1
Overall Study	Ongoing at Data Cut-off Date: 18 March 2021	38	23
Overall Study	Withdrawal by Subject	6	4

Baseline characteristics

Characteristic	AG-120 + Azacitidine	Placebo + Azacitidine	Total
Age, Continuous	74.5 years STANDARD_DEVIATION 6.18	75.2 years STANDARD_DEVIATION 7.39	74.8 years STANDARD_DEVIATION 6.81
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants	1 Participants	7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants	32 Participants	53 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	45 Participants	41 Participants	86 Participants
Race/Ethnicity, Customized Race Asian	15 Participants	19 Participants	34 Participants
Race/Ethnicity, Customized Race Black or African American	0 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Race Not Reported	44 Participants	40 Participants	84 Participants
Race/Ethnicity, Customized Race Other	1 Participants	1 Participants	2 Participants
Race/Ethnicity, Customized Race White	12 Participants	12 Participants	24 Participants
Sex: Female, Male Female	30 Participants	36 Participants	66 Participants
Sex: Female, Male Male	42 Participants	38 Participants	80 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	27 / 71	45 / 73
other Total, other adverse events	68 / 71	72 / 73
serious Total, serious adverse events	49 / 71	60 / 73

Outcome results

Primary

Event-Free Survival (EFS)

EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure was defined as failure to achieve complete remission (CR) by Week 24. CR: Bone marrow blasts \<5% and no Auer rods; absence of extramedullary disease; Absolute neutrophil count (ANC) ≥1.0 × 10\^9 per litre (10\^9/L) (1000 per microlitre \[1000/μL\]); platelet count ≥100 × 10\^9/L (100,000/μL); independence of red blood cell transfusions. Participants who had an EFS event (relapse or death) after, 2 or more missing disease assessments were censored at the last adequate disease assessment documenting no relapse before the missing assessments. The reported data represents the Kaplan-Meier median value.

Time frame: Up to Week 24

Population: FAS included all participants who were randomized.

Arm	Measure	Value (MEDIAN)
AG-120 + Azacitidine	Event-Free Survival (EFS)	0.03 months
Placebo + Azacitidine	Event-Free Survival (EFS)	0.03 months

p-value: 0.001195% CI: [0.16, 0.69]Log Rank

Secondary

Change From Baseline in the EORTC EQ-5D-5L Questionnaire

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.