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

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.

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.

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 + 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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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).

Vital signs will include body temperature, respiratory rate, blood pressure, and heart rate.

LVEF is determined by ECHO or MUGA scan in participants.

Clinical laboratory assessments will include hematology, serum chemistry, coagulation.

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.

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.

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.

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.

Participants receiving concomitant medications will be adequately monitored by ECG controls, drug concentration (where applicable), and serum electrolytes (i.e., potassium and magnesium).

All measures that are indicative of clinical benefit are measured like number of units of platelet and RBC infused.

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.

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.

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.

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.

Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.

Serial blood samples will be drawn before and after dosing of study treatment in order to determine circulating plasma concentrations.