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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: AG-120
* Drug: Placebo
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. Have an isocitrate dehydrogenase 1 (IDH1) mutation. Have an ECOG PS score of 0 to 2. Have adequate hepatic function. Have adequate renal function. Have agreed to undergo serial blood and bone marrow sampling. Be able to understand and willing to sign an informed consent form (ICF). Be willing to complete Quality of Life assessments during the study 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: Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML. Have received any prior treatment for AML with the exception of hydroxyurea. Have received a hypomethylating agent for myelodysplastic syndrome (MDS). 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. 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. 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 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. Have had significant active cardiac disease within 6 months prior to the start of the study treatment. Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia. Have a condition that limits the ingestion or absorption of drugs administered by mouth. 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. 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 participant'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.) Have a known medical history of progressive multifocal leukoencephalopathy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-120 + Azacitidine<br>Participants received AG-120 500 mg orally, once daily (QD) in combination with azacitidine 75 milligrams per square meter per day (mg/m^2/day) subcutaneously (SC) or intravenously (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. | Drug: AG-120<br>* Tablets administered orally<br>* Other names: Ivosidenib;Drug: Azacitidine<br>* Administered SC or IV<br>* Other names: Vidaza®;|
| Placebo Comparator: Placebo + Azacitidine<br>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 . | Drug: Placebo<br>* Tablets administered orally<br>Drug: Azacitidine<br>* Administered SC or IV<br>* Other names: Vidaza®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission Rate (CR Rate) | 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. | Up to approximately 52 months | 
| Overall Survival (OS) | 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. | Up to approximately 52 months | 
| CR + Complete Remission With Partial Hematologic (CRh) Rate | 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. | Up to approximately 52 months | 
| Objective Response Rate (ORR) | 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. | Up to approximately 52 months | 
| CR + CRi (Including CRp) Rate | 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. | Up to approximately 52 months | 
| Duration of CR (DOCR) | 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. | Up to approximately 52 months | 
| Duration of CRh (DOCRh) | 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. | Up to approximately 52 months | 
| Duration of Response (DOR) | 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. | Up to approximately 52 months | 
| Duration of CRi (DOCRi) | 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). | Up to approximately 52 months | 
| Time to CR (TTCR) | 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. | Up to approximately 52 months | 
| Time to CRh (TTCRh) | 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. | Up to approximately 52 months | 
| Time to Response (TTR) | 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. | Up to approximately 52 months | 
| Time to CRi (TTCRi) | 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). | Up to approximately 52 months | 
| Percentage of Participants With Abnormalities in Vital Sign Measurements | Vital signs will include body temperature, respiratory rate, blood pressure, and heart rate. | Up to approximately 52 months | 
| 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 | 
| Percentage of Participants With Abnormalities in Echocardiogram (ECHO) or Multi-Gated Acquisition (MUGA) for Left Ventricular Ejection Fraction (LVEF) | LVEF is determined by ECHO or MUGA scan in participants. | Up to approximately 52 months | 
| Percentage of Participants With Abnormalities in Clinical Laboratory Tests | Clinical laboratory assessments will include hematology, serum chemistry, coagulation. | Up to approximately 52 months | 
| Percentage of Participants With Adverse Events (AEs) | 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. | Up to approximately 52 months | 
| Percentage of Participants With AEs of Special Interest (AESIs) | 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. | Up to approximately 52 months | 
| Percentage of Participants With Serious Adverse Events (SAEs) | 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. | Up to approximately 52 months | 
| Percentage of Participants With Adverse Events Leading to Discontinuation or Death | 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. | Up to approximately 52 months | 
| Percentage of Participants Using Concomitant Medications | Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (i.e., potassium and magnesium). | Up to approximately 52 months | 
| Units of Platelets and Red Blood Cells (RBC) Infused | All measures that are indicative of clinical benefit are measured like number of units of platelet and RBC infused. | Up to approximately 52 months | 
| 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 | 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. | Up to approximately 52 months | 
| 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. | Up to approximately 52 months | 
| Percentage of Participants With CR With IDH1 Mutation Clearance (MC) | 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. | Up to approximately 52 months | 
| Percentage of Participants With Drug Exposure, Dose Modifications and Dose Intensities | 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. | Up to approximately 52 months | 
| Circulating Plasma Concentration of AG-120 | Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations. | Up to approximately 52 months | 
| Circulating Plasma Concentration of 2-HG | Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations. | Up to approximately 52 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia, Leukemia, Azacitidine, AG-120, ivosidenib