A Study to Assess the Safety and Efficacy of Two Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine in Participants With Newly Diagnosed Acute Myeloid Leukemia (AML) Harboring IDH Mutations Who Are Not Candidates to Receive Intensive Induction Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study are to determine the recommended combination dose of AG-120 and AG-221 separately when administered with azacitidine and, to investigate the safety, tolerability, and efficacy of the combinations of AG-120 with azacitidine and AG-221 with azacitidine versus with azacitidine alone in participants with acute myeloid leukemia (AML) with the isocitrate dehydrogenase (IDH) enzyme isoforms 1 or 2 mutations, respectively.

Official Title
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A Phase 1b/2 Open-Label, Randomized Study of 2 Combinations of Isocitrate Dehydrogenase (IDH) Mutant Targeted Therapies Plus Azacitidine: Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus SC Azacitidine in Subjects With Newly Diagnosed Acute Myeloid Leukemia Harboring an IDH1 or an IDH2 Mutation, Respectively, Who Are Not Candidates to Receive Intensive Induction Chemotherapy

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: AG-120
* Drug: Azacitidine
* Drug: AG-221


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed, primary (ie, de novo) or secondary (progression of Myelodysplastic syndrome [MDS] or myeloproliferative neoplasms [MPN], or therapy-related) acute myeloid leukemia (AML) according to the WHO classification with ≥ 20% leukemic blasts in the bone marrow Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Agree to serial bone marrow aspirate/biopsies Exclusion Criteria: Suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype AML secondary to chronic myelogenous leukemia (CML) Received a targeted agent against an isocitrate dehydrogenase 1 (IDH1) or isocitrate dehydrogenase 2 (IDH2) mutation Has or is suspected of having central nervous system (CNS) leukemia. Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is suspected during screening Other protocol defined inclusion/exclusion criteria apply

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AG-120 + Azacitidine<br> | Drug: AG-120<br>* Specified dose on specified days<br>Drug: Azacitidine<br>* Specified dose on specified days<br>|
| Experimental: AG-221 + Azacitidine<br> | Drug: Azacitidine<br>* Specified dose on specified days<br>Drug: AG-221<br>* Specified dose on specified days<br>|
| Experimental: Azacitidine<br> | Drug: Azacitidine<br>* Specified dose on specified days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants Experiencing Dose-limiting Toxicities (DLTs): Phase 1B (Dose Finding Stage) | Dose-limiting toxicities (DLTs) are defined as an event that constitute a change from baseline irrespective of outcome and determined by the investigator to be related to treatment. The DLT-evaluable participants were defined as participants who took at least 1 dose of study drug in the Phase 1b Dose-Finding Stage and either had a DLT during Cycle 1 (regardless of amount of study drug exposure), or had no DLT and completed at least 75% of AG-120 or AG-221 doses (21 out of 28 days) and a minimum of 5 doses of AZA, at least 50% of the planned combination doses for AG-120 or AG-221 and AZA administered together (in the same day for 4 out of 7 days) in the first 28 days from C1D1, and were also considered by the Clinical Study Team to have sufficient safety data available to conclude that a DLT did not occur during Cycle 1. | From first dose to 28 days after first dose | 
| The Number of Participants Experiencing Adverse Events: Phase 1B (Dose Finding and Expansion Stage) | The number of participants experiencing different types of adverse events (AE). An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A Serious Adverse Event (SAE) is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or constitutes an important medical event. Adverse events were analyzed in terms of treatment-emergent AEs (TEAEs). Treatment-emergent adverse events (TEAE) was defined as events that began on or after the start of study drug through 28 days after the last study treatment. The severity/intensity of AEs were graded based upon the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death. | From first dose to 28 days after last dose (up to approximately 13 months) | 
| Overall Response Rate: Phase 2 (Randomized Stage) | The percent of participants with MLFS + CR + CRi + CRp + PR according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria as assessed by investigator. Complete response (CR) and morphologic leukemia-free state (MLFS) are defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. Partial remission (PR) is defined as all hematologic criteria of CR with a >50% decrease in the percentage of BM blasts to 5% to 25%. (<5% considered if Auer rods are present). | From first dose up to approximately 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate: Phase 1B (Dose Finding and Expansion Stage) | Percent of participants with MLFS + CR + CRi + CRp + PR according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria as assessed by investigator. Complete response (CR) and morphologic leukemia-free state (MLFS) are defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. Partial remission (PR) is defined as all hematologic criteria of CR with a >50% decrease in the percentage of BM blasts to 5% to 25%. (<5% considered if Auer rods are present). | From first dose up to approximately 13 months | 
| Sponsor Derived CR and CRh: Phase 1B (Dose Finding and Expansion Stage) | The percent of participants with morphologic complete remission (CR) and morphologic complete remission with partial hematologic recovery (CRh) based on laboratory data. CR is defined as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease. Plus, all the following conditions should be met: ANC ≥ 1 x 109/L (1,000/μL), platelet count ≥ 100 x 109/L (100,000/μL), independent of red cell transfusions for ≥ 1 week immediately before each response assessment. CRh is defined as less than 5% blasts in a BM aspirate sample with marrow spicules plus ANC > 500 x 109/L (1,000/μL) & Platelet count > 50 x 109/L (100,000/μL). CRh is defined as Response of bone marrow blast <5% with absolute neutrophil count (ANC) > 0.5 × 10^9/L and platelet > 50 × 10^9/L. | From first dose up to approximately 13 months | 
| Event-free Survival (EFS): Phase 2 (Randomized Stage) | Event-Free Survival is the time from date of randomization to the date of documented morphologic relapse, progression, or death from any cause, whichever occurs first. Morphologic Relapse is defined as either reappearance of ≥ 5% blasts in the BM not attributable to any other cause or the development of extramedullary disease. Progression is defined as a > 50% increase of BM blast count percentage from baseline to ≥ 20% for participants with 5 to 70% BM blasts at baseline or a doubling of absolute blast count in peripheral blood from baseline to ≥ 10 x 109/L (10,000/μL) for participants with > 70% BM blasts at baseline or the development of new extramedullary disease. | From randomization to the date of documented relapse, progression, or death due to any cause, whichever occurs first (up to approximately 26 months) | 
| The Number of Participants Experiencing Adverse Events: Phase 2 (Randomized Stage) | The number of participants experiencing different types of adverse events (AE). An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A Serious Adverse Event (SAE) is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and/or constitutes an important medical event. Adverse events were analyzed in terms of treatment-emergent AEs (TEAEs). Treatment-emergent adverse events (TEAE) was defined as events that began on or after the start of study drug through 28 days after the last study treatment. The severity/intensity of AEs were graded based upon the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death. | From first dose to 28 days after last dose (up to approximately 26 months) | 
| Complete Remission Rate: Phase 2 (Randomized Stage) | The percent of participants with morphologic complete remission (CR) according to modified International Working Group Acute Myeloid Leukemia Response Criteria (IWG AML). CR is defined as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease; plus the following conditions: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. | From first dose up to approximately 26 months | 
| Hematologic Improvement (HI) Rate: Phase 2 (Randomized Stage) | The percent of participants with hematologic improvement neutrophil response (HI-N) + hematologic improvement platelet response (HI-P) + hematologic improvement erythroid response (HI-E) according to the International Working Group for Myelodysplastic Syndromes for Hematologic Improvement (IWG MDS HI) criteria. HI-E is defined as a hemoglobin increase by ≥ 1.5 g/dL and a relevant reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 week compared with the pretreatment transfusion number in the previous 8 week. HI-P is defined as an absolute increase of ≥ 30 X 10^9/L for participants starting with > 20 X and an increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-N is defined as At least 100% increase and an absolute increase > 0.5 X 10^9/L. | From first dose up to approximately 26 months | 
| Duration of Response: Phase 2 (Randomized Stage) | The time from first documented CR/CRi/CRp/PR/MLFS to documented morphologic relapse, progression, or death due to any cause, whichever occurred first. CR and MLFS are defined as <5% blasts in a BM aspirate sample with marrow spicules + a count of ≥200 nucleated cells with no blasts with Auer rods + no extramedullary disease. CR must also include: ANC ≥ 1,000/μL, Platelet count ≥100,000/μL, + independent of red cell transfusions for ≥1 week before assessment. CRi is all criteria of CR except ANC. CRp is all criteria of CR except platelet count. PR is defined as all hematologic criteria of CR with >50% decrease in BM blasts to 5%-25%. Relapse is defined as reappearance of ≥ 5% blasts in the BM not attributable to other cause or development of extramedullary disease. Progression is defined as > 50% increase of BM blast count from baseline to ≥ 20% or a doubling of absolute blast count in peripheral blood from baseline to ≥ 10,000/μL or development of new extramedullary disease. | From first dose up to approximately 26 months | 
| Time to Response: Phase 2 (Randomized Stage) | Time from first dose of study drug to first documented MLFS/CR/CRi/CRp/PR according to modified IWG AML response criteria. Complete remission (CR) and morphologic leukemia-free state (MLFS) are defined as <5% blasts in a BM aspirate sample with marrow spicules and a count of ≥200 nucleated cells. There should be no blasts with Auer rods and no extramedullary disease. CR must also include the following conditions: absolute neutrophil count (ANC) ≥1,000/μL, Platelet count ≥100,000/μL, and independent of red cell transfusions for ≥1 week before each response assessment. Complete remission with incomplete neutrophil recovery (CRi) is all criteria of CR except ANC. Complete remission with incomplete platelet recovery (CRp) is all criteria of CR except platelet count. partial remission (PR) is defined as all hematologic criteria of CR with a >50% decrease in the percentage of BM blasts to 5% to 25%. (<5% considered if Auer rods are present). | From first dose to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 26 months) | 
| Overall Survival: Phase 2 (Randomized Stage) | Overall survival (OS) is defined as time from randomization to death due to any cause. | From randomization to date of death (up to approximately 26 months) | 
| One Year Survival Rate: Phase 2 (Randomized Stage) | The percent of participants alive at 1 year from randomization | From randomization to 1 year after randomization | 
| AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 1B (Expansion Stage) | Area under the plasma concentration-time curve from time zero to 8 hours, calculated using the linear trapezoid rule. | Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2 | 
| Cmax- Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage) | Cmax: Maximum observed plasma concentration, obtained directly from the observed concentration versus time data | Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2 | 
| Tmax- Time of Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage) | Tmax: Time of maximum observed plasma concentration, obtained directly from the observed concentration versus time data. | Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2 | 
| AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage) | Area under the plasma concentration-time curve from time zero to 8 hours, calculated using the linear trapezoid rule. | Pre-dose, 2, 3, 4, 6, and 8 hours post dose (± 10 minutes) on day 1 of cycle 2 | 
| AUC (0-24)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage) | AUC0-24: Area under the plasma concentration-time curve from time zero to 24 hours, calculated using the linear trapezoid rule. | Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2 | 
| Cmax- Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage) | Cmax: Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. | Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2 | 
| Tmax- Time of Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage) | Tmax: Time of maximum observed plasma concentration, obtained directly from the observed concentration versus time data. | Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2 | 
| Change From Baseline in Health-related Quality-of-Life Domain Scores of the EORTC QLQ-C30: Phase 2 (Randomized Stage) | The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning. Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher scores on symptom scales indicating worse symptoms. Baseline results are obtained just prior to the start of study treatment on Day 1 of Cycle 1 and will serve as the baseline values. EORTC QLQ-C30 is assessed prior to dosing and prior to interaction with study personnel. | Baseline and Day 1 Cycle 5 | 
| Change From Baseline in Health Utility Indices of the EQ-5D-5L: Phase 2 (Randomized Stage) | The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. These health states are converted to a single index value using the crosswalk method to the EQ-5D-3L value set from the United Kingdom (UK). The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility. Baseline results are obtained just prior to the start of study treatment on Day 1 of Cycle 1 and will serve as the baseline values. | Baseline and Day 1 Cycle 5 | 
| Change From Baseline in Visual Analogue Scale (VAS) Scores of the EQ-5D-5L: Phase 2 (Randomized Stage) | The European Quality of Life 5D-5L (EQ-5D-5L) instrument has a respondent's self-rated today's health scale which is recorded on a VAS with endpoints labeled the best health you can imagine and the worst health you can imagine. The scale is numbered from 0 to 100 with 0 corresponding to the worst imaginable health state and 100 corresponding to the best imaginable health state. A high score represents a better level of QoL. Baseline results are obtained just prior to the start of study treatment on Day 1 of Cycle 1 and will serve as the baseline values. | Baseline and Day 1 Cycle 5 | 
| Sponsor Derived CR: Phase 2 (Randomized Stage) | The number of participants with Morphologic Complete Remission (CR) based on laboratory data. CR is defined as as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease. Plus, all the following conditions should be met: ANC ≥ 1 x 109/L (1,000/μL), platelet count ≥ 100 x 109/L (100,000/μL), independent of red cell transfusions for ≥ 1 week immediately before each response assessment. | From first dose to end of study | 
| Sponsor Derived CR and CRh: Phase 2 (Randomized Phase) | The number of participants with morphologic complete remission (CR) and morphologic complete remission with partial hematologic recovery (CRh) based on laboratory data. CR is defined as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease. Plus, all the following conditions should be met: ANC ≥ 1 x 109/L (1,000/μL), platelet count ≥ 100 x 109/L (100,000/μL), independent of red cell transfusions for ≥ 1 week immediately before each response assessment. CRh is defined as Response of bone marrow blast <5% with absolute neutrophil count (ANC) > 0.5 × 10^9/L and platelet > 50 × 10^9/L. | From first dose to end of study | 
| Time to Sponsor Derived CR and CRh: Phase 2 (Randomized Phase) | Time from first dose of study drug to first documented CR/CRh. Morphologic Complete Remission (CR) is defined as as less than 5% blasts in a BM aspirate sample with marrow spicules and with a count of at least 200 nucleated cells. There should be no blasts with Auer rods and absence of extramedullary disease. Plus, all the following conditions should be met: ANC ≥ 1 x 109/L (1,000/μL), platelet count ≥ 100 x 109/L (100,000/μL), independent of red cell transfusions for ≥ 1 week immediately before each response assessment. Morphologic complete remission with partial hematologic recovery (CRh) is defined as less than 5% blasts in a BM aspirate sample with marrow spicules plus ANC > 500 x 109/L (1,000/μL) & Platelet count > 50 x 109/L (100,000/μL). | From first dose to end of study | 
| Duration of Sponsor Derived CR/CRh: Phase 2 (Randomized Stage) | Time from first documented CR/CRh to documented morphologic relapse, PD, or death due to any cause, whichever occurred first. Participants without morphologic relapse, PD, or death due to any cause were censored at the date of the last response assessment. Morphologic Relapse is defined as either reappearance of ≥ 5% blasts in the BM not attributable to any other cause or the development of extramedullary disease. Progression (PD) is defined as a > 50% increase of BM blast count percentage from baseline to ≥ 20% for participants with 5 to 70% BM blasts at baseline or a doubling of absolute blast count in peripheral blood from baseline to ≥ 10 x 109/L (10,000/μL) for participants with > 70% BM blasts at baseline or the development of new extramedullary disease. | From first dose to end of study | 

 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, AG-221