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

JRCT ID: jRCT2051240135

Registered date:26/09/2024

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Acute Myeloid Leukemia (AML)
• Date of first enrollment: 12/02/2019
• Target sample size: 10
• Countries of recruitment: Australia,Japan,Austria,Japan,Brazil,Japan,Canada,Japan,China,Japan,Czechia,Japan,France,Japan,Germany,Japan,Israel,Japan,Italy,Japan,Korea,Japan,Mexico,Japan,Netherlands,Japan,Poland,Japan,Russian Federation,Japan,Spain,Japan,Taiwan,Japan,United Kingdom,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

AG-120 + AZA arm:
- AG-120 (500 mg) will be administered orally QD (approximately every 24 hours) during Weeks 1 to 4 in continuous 4-week cycles.
- Azacitidine (75 mg/m2/day) is administered by SC or IV in the first week of each 4-week cycles.
Placebo + AZA arm:
- Placebo will be administered orally QD (approximately every 24 hours) during Weeks 1 to 4 in continuous 4-week (28-day) cycles.
- Azacitidine (75 mg/m2/day) is administered by SC or IV in the first week of each 4-week period.

Outcome(s)

• Primary Outcome: The primary endpoint of the study is EFS (Event-free survival) will be followed every Day 1 (plus-minus 7 days) of Weeks 9, 17, 25, 33, 41, 53, and every 24 weeks thereafter

Secondary Outcome

- CR (Complete remission) rate
- OS (Overall survival)
- CR (Complete remission) + CRh (Complete remission with partial hematologic recovery)
- ORR (Objective response rate)

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Be >=18 years of age and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC):
a. >=75 years old
b. ECOG PS = 2
c. Severe cardiac disorder (eg, congestive heart failure requiring treatment, LVEF <=50 percents, or chronic stable angina)
d. Severe pulmonary disorder (eg, diffusing capacity of the lungs for carbon monoxide <=65 percents or forced expiratory volume in 1 second <=65 percents)
e. Creatinine clearance <45 mL/minute
f. Bilirubin >1.5 times upper limit of normal (x ULN)
g. Any other comorbidity that the Investigator judges to be incompatible with intensive IC must be reviewed and approved by the Medical Monitor before study enrollment.
2. Have previously untreated AML, defined according to World Health Organization criteria. 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.
4. Have an ECOG PS score of 0 to 2.
5. Have adequate hepatic function, as evidenced by:
a. Serum total bilirubin <=2 x ULN, unless considered to be due to Gilberts disease or underlying leukemia, where it must be <3 x ULN.
b. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) <=3.0 x ULN, unless considered to be due to underlying leukemia.
6. Have adequate renal function, as evidenced by serum creatinine <=2.0 x ULN or creatinine clearance 30 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. In countries where the age of consent is greater than 18 years, for subjects under the age of consent, both the subject and his/her guardian or legal representative must be willing to sign an informed consent form.
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 with female partners of reproductive potential, must use 2 effective forms of contraception (including at least 1 barrier form) approved by a local regulatory authority 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. Coadministration of AG-120 may decrease the concentrations of hormonal contraceptives.

Exclude criteria

1. Are candidates for intensive 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 treatment for an antecedent hematologic disorder, including investigational agents, may not be randomized until a washout period of at least 5 half-lives of the investigational 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, even if they interrupt 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. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
10. 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
11. Have had significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association Class (NYHA) Class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke.
12. Have a heart-rate corrected QT interval using Fridericias method (QTcF) >=470 msec or any other factor that increases the risk of QT prolongation or arrhythmic events (eg, NYHA Class III or IV congestive 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.
13. Have a known infection caused by human immunodeficiency virus or active hepatitis B virus (HBV) or hepatitis C virus that cannot be controlled by treatment.
14. Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.
15. Have uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg).
16. 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.
17. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
18. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the subjects ability to give informed consent or participate in the study.
19. 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.)
20. Subjects with a known medical history of progressive multifocal leukoencephalopathy.

Related Information

• Primary Sponsor: Kamemura Nobuto
• Secondary ID(s): NCT03173248