Phase 3 Multicenter Double-Blind Randomized Study of Ivosidenib and Azacitidine in Untreated IDH1-Mutated Acute Myeloid Leukemia Patients Aged ≥18 Years
- Trial ID
- 2024-514309-73-00
- Protocol
- AG120-C-009
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 3, multicenter, double-blind, randomized, placebo-controlled study is to compare **event-free survival (EFS)** between the combination of AG-120 (ivosidenib) and azacitidine versus placebo and azacitidine in subjects aged 18 years and older with previously untreated **acute myeloid leukemia (AML)** with an **IDH1 mutation**. This objective is clinically relevant as EFS is a critical endpoint in assessing the efficacy of new therapeutic regimens in prolonging the time patients remain free from events such as disease progression or relapse.
The secondary objectives include:
- Comparing the complete remission (CR) rate between AG-120 + azacitidine and placebo + azacitidine.
- Comparing overall survival (OS) between AG-120 + azacitidine and placebo + azacitidine.
- Comparing the CR + complete remission with partial hematologic recovery (CRh) rate between AG-120 + azacitidine and placebo + azacitidine, with CRh being derived by the sponsor.
- Comparing the objective response rate (ORR) between AG-120 + azacitidine and placebo + azacitidine.
Participants
The clinical trial involves a total of **65 participants** diagnosed with **previously untreated acute myeloid leukemia** with an **IDH1 mutation**. The study population includes both male and female subjects aged **18 years and older**, with a specific focus on individuals who are ineligible for intensive induction chemotherapy due to factors such as age (≥75 years), performance status, or comorbid conditions. Participants were selected based on their diagnosis and genetic mutation status, confirmed through central laboratory testing. The trial does not include a vulnerable population. Participants are expected to maintain their usual lifestyle, with no specific dietary or physical activity requirements outlined. Key inclusion criteria include adequate hepatic and renal function, as well as the ability to provide informed consent and comply with study procedures. The trial aims to assess event-free survival between treatment groups, with no significant lifestyle modifications required from participants.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of AG-120 in combination with **azacitidine** in subjects aged 18 years and older with previously untreated **acute myeloid leukemia** (AML) with an IDH1 mutation. The primary objective is to compare event-free survival (EFS) between the treatment group receiving AG-120 plus azacitidine and the control group receiving placebo plus azacitidine. The trial is expected to run from June 20, 2017, to June 30, 2026, with the primary endpoint being the time from randomization until treatment failure, relapse from remission, or death from any cause.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, IDH1 mutation status, and overall health. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include assessments such as blood and bone marrow sampling, quality of life evaluations, and safety monitoring. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.
The expected length of participant involvement is up to 24 weeks, with conditions for early termination including treatment failure, adverse events, or withdrawal of consent. Participants must meet specific inclusion criteria, such as having an ECOG performance status of 0 to 2 and adequate hepatic and renal function. Exclusion criteria are not explicitly detailed in the provided data. The study involves the administration of AG-120 as a film-coated tablet for oral use and azacitidine as a powder for suspension for injection, with a placebo to match AG-120 for the control group.
Treatment
The clinical trial involves the administration of **ivosidenib**, marketed as AG-120/S95031, which is provided in the form of a **film-coated tablet**. Each tablet contains 250 mg of the active substance. The medication is administered orally, with a maximum daily dose of 500 mg. The treatment period is limited to one cycle, with the dosing schedule determined by the study protocol. Participant compliance is monitored through regular assessments and pill counts to ensure adherence to the prescribed regimen.
In addition to ivosidenib, the study includes the administration of **azacitidine**, marketed as Vidaza. This medication is supplied as a **powder for suspension for injection**, with a concentration of 25 mg/ml. Azacitidine is administered intravenously, with a maximum daily dose of 75 mg/m². The treatment period is also limited to one cycle. The dosing schedule is aligned with the study protocol, and participant compliance is monitored through infusion records and regular follow-up visits.
The study also utilizes a **placebo** to match the AG-120 tablet, which is supplied as a film-coated tablet for oral administration. The placebo is designed to mimic the appearance and administration route of the active medication, ensuring the double-blind nature of the trial. Compliance with placebo administration is monitored similarly to the active treatments, using pill counts and participant diaries.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **event-free survival (EFS)**, which is defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is specifically defined as the failure to achieve complete remission (CR) by Week 24. Secondary endpoints include the CR rate, overall survival (OS), CR + CRh rate, and overall response rate (ORR). The CR rate is characterized by bone marrow blasts less than 5%, absence of Auer rods, no extramedullary disease, an absolute neutrophil count (ANC) of at least 1.0 × 109/L, a platelet count of at least 100 × 109/L, and independence from red blood cell transfusions. OS is measured from the date of randomization to the date of death from any cause. The CR + CRh rate includes CR with partial recovery of peripheral blood counts, where ANC is greater than 0.5 × 109/L and platelet count is greater than 50 × 109/L. ORR encompasses the rates of CR, CRi (including CRp), partial remission (PR), and morphologic leukemia-free state (MLFS).
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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%, or chronic stable angina) d. Severe pulmonary disorder (eg, diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%) e. Creatinine clearance <45 mL/minute f. Bilirubin >1.5 times upper limit of normal (× 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.
- 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.
- 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 (or peripheral blood sample if bone marrow aspirate is not available, with Medical Monitor approval). (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. Bone marrow aspirate [or peripheral blood sample if bone marrow aspirate is not available, with Medical Monitor approval] for central laboratory testing must have been sent with proof of shipment to the central laboratory prior to randomization.)
- Have an ECOG PS score of 0 to 2.
- Have adequate hepatic function, as evidenced by: a. Serum total bilirubin ≤2 × 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.
- Have adequate renal function, as evidenced by serum creatinine ≤2.0 × ULN or creatinine clearance >30 mL/min based on the Cockcroft-Gault glomerular filtration rate.
- Have agreed to undergo serial blood and bone marrow sampling.
- Be able to understand and willing to sign an informed consent form.
- Be willing to complete QoL assessments during study treatment and at the designated time points following treatment discontinuation.
- 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) 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.
Exclusion Criteria
- Are candidates for intensive IC for their AML.
- Have received any prior treatment for AML with the exception of nononcolytic treatments to stabilize disease such as hydroxyurea or leukapheresis.
- Have received a hypomethylating agent for myelodysplastic syndrome (MDS).
- 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.
- Have received prior treatment with an IDH1 inhibitor.
- Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.
- Are female and pregnant or breastfeeding.
- 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.
- Exclusion Criterion #9 was removed in Protocol Amendment 5, Version 6.0.
- Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.
- 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
- 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.
- 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, 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.
- 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.
- Have dysphagia, short-gut syndrome, gastroparesis, or any other condition that limits the ingestion or gastrointestinal absorption of orally administered drugs.
- Have uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg).
- 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.
- Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.
- 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.
- 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.)
- Subjects with a known medical history of progressive multifocal leukoencephalopathy.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 20 Jun 2017 | 24 |
 Germany | Not Recruiting | 20 Jun 2017 | 12 |
 Italy | Not Recruiting | 20 Jun 2017 | 10 |
 Poland | Not Recruiting | 20 Jun 2017 | 9 |
 Spain | Not Recruiting | 20 Jun 2017 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
AG-120/S95031 250mg film-coated tablet | Test | FILM-COATED TABLET | ORAL USE | 500 | 1 | PRD10101805 |
Placebo to Match AG-120 Tablet, 250 mg, is supplied as a film-coated tablet for oral
administration. | Placebo | N/A | — | — | — | N/A |
Vidaza 25 mg/ml powder for suspension for injection | Test | POWDER FOR SUSPENSION FOR INJECTION | INTRAVENOUS | 75 | 1 | PRD9244549 |