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

• ClinicalTrials.gov Identifier: NCT02677922
• Recruitment Status: Active, not recruiting
• First Posted: February 9, 2016
• Results First Posted: November 22, 2022
• Last Update Posted: January 25, 2024
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: February 5, 2016
• First Posted Date: February 9, 2016
• Results First Submitted Date: September 2, 2022
• Results First Posted Date: November 22, 2022
• Last Update Posted Date: January 25, 2024
• Actual Study Start Date: June 3, 2016
• Actual Primary Completion Date: August 2, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 28, 2022)

• The Number of Participants Experiencing Dose-limiting Toxicities (DLTs): Phase 1B (Dose Finding Stage) [ Time Frame: From first dose to 28 days after first dose ]
  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.
• The Number of Participants Experiencing Adverse Events: Phase 1B (Dose Finding and Expansion Stage) [ Time Frame: From first dose to 28 days after last dose (up to approximately 13 months) ]
  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.
• Overall Response Rate: Phase 2 (Randomized Stage) [ Time Frame: From first dose up to approximately 26 months ]
  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).

Original Primary Outcome Measures (submitted: February 5, 2016)

• Dose limiting toxicities (DLTs)-Phase 1B [ Time Frame: Up to approximately 7 months ]
  DLTs will be defined as any of the following events that commence within 28 days of the first dose of IP in a 28-day treatment cycle, constitute a change from baseline irrespective of outcome and are determined by the investigator to be related to treatment.
• Adverse Events (AEs) in Ph 1b [ Time Frame: Up to approximately 4 years ]
  Number of participants with adverse events
• Pharmacokinetics- Cmax [ Time Frame: Up to approximately 7 months ]
  Maximum observed concentration in plasma
• Pharmacokinetics- Tmax [ Time Frame: Up to approximately 7 months ]
  Time to maximum concentration
• Pharmacokinetics- AUC [ Time Frame: Up to approximately 7 months ]
  Area under the plasma concentration-time curve
• Overall response rate (ORR)Ph 2 [ Time Frame: Up to approximately 30 months ]
  Includes responses of Morphologic complete remission (CR), Morphologic complete remission with incomplete platelet recovery (CRp), morphologic leukemia-free state (MLFS), Morphologic complete remission with incomplete neutrophil recovery (CRi), and Partial remission (PR), according to modified International

Current Secondary Outcome Measures (submitted: October 28, 2022)

• Overall Response Rate: Phase 1B (Dose Finding and Expansion Stage) [ Time Frame: From first dose up to approximately 13 months ]
  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).
• Sponsor Derived CR and CRh: Phase 1B (Dose Finding and Expansion Stage) [ Time Frame: From first dose up to approximately 13 months ]
  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.
• Event-free Survival (EFS): Phase 2 (Randomized Stage) [ Time Frame: From randomization to the date of documented relapse, progression, or death due to any cause, whichever occurs first (up to approximately 26 months) ]
  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.
• The Number of Participants Experiencing Adverse Events: Phase 2 (Randomized Stage) [ Time Frame: From first dose to 28 days after last dose (up to approximately 26 months) ]
  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.
• Complete Remission Rate: Phase 2 (Randomized Stage) [ Time Frame: From first dose up to approximately 26 months ]
  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.
• Hematologic Improvement (HI) Rate: Phase 2 (Randomized Stage) [ Time Frame: From first dose up to approximately 26 months ]
  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.
• Duration of Response: Phase 2 (Randomized Stage) [ Time Frame: From first dose up to approximately 26 months ]
  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.
• Time to Response: Phase 2 (Randomized Stage) [ Time Frame: From first dose to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 26 months) ]
  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).
• Overall Survival: Phase 2 (Randomized Stage) [ Time Frame: From randomization to date of death (up to approximately 26 months) ]
  Overall survival (OS) is defined as time from randomization to death due to any cause.
• One Year Survival Rate: Phase 2 (Randomized Stage) [ Time Frame: From randomization to 1 year after randomization ]
  The percent of participants alive at 1 year from randomization
• AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 1B (Expansion Stage) [ Time Frame: Pre-dose, 0.5, 2, 3, 4, 6, 8 hours post dose (± 10 minutes) on day 1 of cycle 1 and 2 ]
  Area under the plasma concentration-time curve from time zero to 8 hours, calculated using the linear trapezoid rule.
• Cmax- Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage) [ Time Frame: 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, obtained directly from the observed concentration versus time data
• Tmax- Time of Maximum Observed Plasma Concentration: Phase 1B (Expansion Stage) [ Time Frame: 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, obtained directly from the observed concentration versus time data.
• AUC (0-8)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage) [ Time Frame: Pre-dose, 2, 3, 4, 6, and 8 hours post dose (± 10 minutes) on day 1 of cycle 2 ]
  Area under the plasma concentration-time curve from time zero to 8 hours, calculated using the linear trapezoid rule.
• AUC (0-24)- Area Under the Plasma Concentration-Time Curve: Phase 2 (Randomized Stage) [ Time Frame: Pre-dose, 2, 3, 4, 6, 8, and 24 hours post dose (± 10 minutes) on day 1 of cycle 2 ]
  AUC0-24: Area under the plasma concentration-time curve from time zero to 24 hours, calculated using the linear trapezoid rule.
• Cmax- Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage) [ Time Frame: 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, obtained directly from the observed concentration versus time data.
• Tmax- Time of Maximum Observed Plasma Concentration: Phase 2 (Randomized Stage) [ Time Frame: 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, obtained directly from the observed concentration versus time data.
• Change From Baseline in Health-related Quality-of-Life Domain Scores of the EORTC QLQ-C30: Phase 2 (Randomized Stage) [ Time Frame: Baseline and Day 1 Cycle 5 ]
  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.
• Change From Baseline in Health Utility Indices of the EQ-5D-5L: Phase 2 (Randomized Stage) [ Time Frame: Baseline and Day 1 Cycle 5 ]
  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.
• Change From Baseline in Visual Analogue Scale (VAS) Scores of the EQ-5D-5L: Phase 2 (Randomized Stage) [ Time Frame: Baseline and Day 1 Cycle 5 ]
  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.
• Sponsor Derived CR: Phase 2 (Randomized Stage) [ Time Frame: From first dose to end of study ]
  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.
• Sponsor Derived CR and CRh: Phase 2 (Randomized Phase) [ Time Frame: From first dose to end of study ]
  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.
• Time to Sponsor Derived CR and CRh: Phase 2 (Randomized Phase) [ Time Frame: From first dose to end of study ]
  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).
• Duration of Sponsor Derived CR/CRh: Phase 2 (Randomized Stage) [ Time Frame: From first dose to end of study ]
  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.

Original Secondary Outcome Measures (submitted: February 5, 2016)

• Overall Response Rate - Phase 1b (Ph 1b) [ Time Frame: Up to approximately 13 months ]
  Rate of Morphologic leukemia-free state (MLFS) + Morphologic complete remission (CR) + Morphologic complete remission with incomplete neutrophil recovery (CRi) + Morphologic complete remission with incomplete platelet recovery (CRp) + Partial remission (PR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
• Event-Free Survival - Phase 2 (Ph 2) [ Time Frame: Up to approximately 30 months ]
  Time from randomization to documented morphologic relapse, progression according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria, or death from any cause, whichever occurs first.
• Adverse Events (AEs) - Ph 2 [ Time Frame: Up to approximately 4 years ]
  Number of participants with adverse events
• Complete remission rate - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Rate of morphologic complete remission (CR) according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria
• Hematologic improvement rate - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Rate of Hematologic improvement - neutrophil response (HI-N) + Hematologic improvement - platelet response (HI-P) + Hematologic improvement - erythroid response (HI-E) according to International Working Group (IWG) Myelodysplastic syndromes (MDS) Hematologic improvement(HI) criteria
• Duration of Response - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, progression according to modified IWG AML response criteria, or death due to any cause, whichever occurs first
• Overall Survival - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Time from randomization to death due to any cause
• One-year survival- Ph 2 [ Time Frame: Up to approximately 12 months ]
  The probability of survival at 1 year from randomization
• Pharmacokinetics- Cmax - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Maximum observed concentration in plasma
• Pharmacokinetics- Tmax - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Time to maximum concentration
• Pharmacokinetics- AUC - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Area under the plasma concentration-time curve
• EORTC QLQ-C30 - European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Is a validated quality-of-life measure applicable to subjects with any cancer diagnosis. It 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
• EQ-5D-5L Health Questionnaire - Ph 2 [ Time Frame: Up to approximately 30 months ]
  Is a standardized instrument for use as a measure of health outcome. It provides a simple descriptive profile and a single index value for health status, and is applicable to a wide range of health conditions and treatments

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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

Brief Summary

The purpose of this study are

1. to determine the recommended combination dose of AG-120 and AG-221 separately when administered with azacitidine and,
2. 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Leukemia, Myeloid, Acute

Intervention

• Drug: AG-120
  Specified dose on specified days
• Drug: Azacitidine
  Specified dose on specified days
• Drug: AG-221
  Specified dose on specified days

Study Arms

• Experimental: AG-120 + Azacitidine
  Interventions:

  • Drug: AG-120
  • Drug: Azacitidine
• Experimental: AG-221 + Azacitidine
  Interventions:

  • Drug: Azacitidine
  • Drug: AG-221
• Experimental: Azacitidine
  Intervention: Drug: Azacitidine

Publications *

• DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S, Zeidan AM, Fathi AT, Kantarjian HM, Bennett JM, Frattini MG, Martin-Regueira P, Lersch F, Gong J, Hasan M, Vyas P, Dohner H. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021 Nov;22(11):1597-1608. doi: 10.1016/S1470-2045(21)00494-0. Epub 2021 Oct 18.
• DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, Dohner H, Martinelli G, Patel PA, Raffoux E, Tan P, Zeidan AM, de Botton S, Kantarjian HM, Stone RM, Frattini MG, Lersch F, Gong J, Gianolio DA, Zhang V, Franovic A, Fan B, Goldwasser M, Daigle S, Choe S, Wu B, Winkler T, Vyas P. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia. J Clin Oncol. 2021 Jan 1;39(1):57-65. doi: 10.1200/JCO.20.01632. Epub 2020 Oct 29. Erratum In: J Clin Oncol. 2021 Feb 1;39(4):341.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: October 28, 2022): 130
• Original Estimated Enrollment (submitted: February 5, 2016): 150
• Estimated Study Completion Date: October 31, 2024
• Actual Primary Completion Date: August 2, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Italy, Korea, Republic of, Netherlands, Portugal, Spain, Sweden, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT02677922
• Other Study ID Numbers: AG-221-AML-005; 2015-003951-23 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Celgene Corporation
• Current Study Sponsor: Celgene
• Original Study Sponsor: Celgene Corporation
• Collaborators: Not Provided

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: January 2024