An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation (IDHENTIFY)

• ClinicalTrials.gov Identifier: NCT02577406
• Recruitment Status: Active, not recruiting
• First Posted: October 16, 2015
• Results First Posted: September 10, 2022
• Last Update Posted: May 3, 2023
• Sponsor: Celgene
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: October 14, 2015
• First Posted Date: October 16, 2015
• Results First Submitted Date: June 29, 2022
• Results First Posted Date: September 10, 2022
• Last Update Posted Date: May 3, 2023
• Actual Study Start Date: December 30, 2015
• Actual Primary Completion Date: March 17, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 17, 2022)

Overall Survival (OS) [ Time Frame: From randomization to death due to any cause (up to approximately 49 months) ]

The time between randomization and death from any cause. Participants who drop-out or are alive at the end of trial will have their OS times censored at the time of last contact, as appropriate.

Original Primary Outcome Measures (submitted: October 14, 2015)

Overall survival [ Time Frame: Up to approximatly 28 months ]

Time from randomization to death due to any cause

Current Secondary Outcome Measures (submitted: August 17, 2022)

• Overall Response Rate [ Time Frame: From randomization up to approximately 49 months ]
  Number of participants with MLFS + CR + CRi + CRp + PR according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria. 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).
• Event-Free Survival [ Time Frame: From randomization to the date of documented morphologic relapse after CR/CRi/CRp, PD or death from any cause, whichever occurs first. (up to approximately 49 months) ]
  Time from randomization to documented morphologic relapse after complete remission/complete remission with incomplete neutrophil recovery/complete remission with incomplete platelet recovery (CR/CRi/CRp), progressive disease (PD) or death from any cause, whichever occurs first. Morphologic Relapse after CR/CRi/CRp is defined as either reappearance of ≥ 5% blasts in the BM not attributable to any other cause or the development of extramedullary disease. 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.
• Duration of Response [ Time Frame: From randomization to documented morphologic relapse after CR/CRi/CRp/ PD or death due to any cause, whichever occurs first (up to approximately 49 months) ]
  Time from first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse after CR/CRi/CRp/ PD or death due to any cause, whichever occurs 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 after CR/CRi/CRp is defined as reappearance of ≥ 5% blasts in the BM not attributable to other cause or development of extramedullary disease. PD 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 [ Time Frame: From randomization to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 49 months) ]
  Time from randomization to first documented MLFS/CR/CRi/CRp/PR. 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).
• Treatment Mortality at 30 Days [ Time Frame: From first dose to 30 days after first dose ]
  The number of participant deaths from any cause within 30 days of initiation of study treatment.
• Treatment Mortality at 60 Days [ Time Frame: From first dose to 60 days after first dose ]
  The number of participant deaths from any cause within 60 days of initiation of study treatment.
• One-Year Survival Rate [ Time Frame: From randomization to 1 year after randomization ]
  The proportion of participants alive at 1 year after randomization
• Overall Remission Rate [ Time Frame: From randomization up to approximately 49 months ]
  The number of participants with CR + CRi + CRp according to modified International Working Group Acute Myeloid Leukemia (IWG AML) response criteria. Complete remission (CR) is 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.
• Complete Remission Rate [ Time Frame: From randomization up to approximately 49 months ]
  The number 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 Rate [ Time Frame: From randomization up to approximately 49 months ]
  The number 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.
• The Number of Participants That Underwent Hematopoietic Stem Cell Transplantation (HSCT) [ Time Frame: From randomization up to approximately 49 months ]
  The number of participants that underwent hematopoietic stem cell transplantation during the study.
• Time to Treatment Failure [ Time Frame: From randomization to discontinuation of study treatment due to any cause (up to approximately 49 months) ]
  Time from randomization to discontinuation of study treatment due to any cause
• The Number of Participants Experiencing Adverse Events (AEs) [ Time Frame: From first dose up to 28 days after last dose (up to approximately 49 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, or constitutes an important medical event. All AEs were coded using the MedDRA Version 22.0. Adverse events were analyzed in terms of treatment-emergent AEs (TEAEs). A treatment-related TEAE was defined as a TEAE that was suspected by the investigator to be related to study treatment. The severity was graded by the study personnel based on NCI National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
• The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Serum Chemistry [ Time Frame: From first dose up to approximately 49 months ]
  The percent of participants with clinically significant serum chemistry laboratory abnormalities. A clinically significant laboratory abnormality is defined as meeting Grade 3 or Grade 4 criteria according to the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is defined as severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4 is defined as life-threatening consequences; urgent intervention indicated. The chemistry panel includes sodium, potassium, calcium, magnesium, chloride, phosphorus, CO2, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline phosphatase (ALP), bilirubin (total and direct), uric acid, lactate dehydrogenase (LDH), AST/SGOT, ALT/SGPT, gamma glutamyl transpeptidase (GGT), amylase and lipase.
• The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Hematology [ Time Frame: From first dose up to approximately 49 months ]
  The percent of participants with clinically significant hematology laboratory abnormalities. A clinically significant laboratory abnormality is defined as meeting Grade 3 or Grade 4 criteria according to the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 is defined as severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care. Grade 4 is defined as life-threatening consequences; urgent intervention indicated. The hematology panel includes complete blood count (CBC) with differential, including red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell (WBC) count (with differential), absolute neutrophil count (ANC) and platelet count.
• The Percent of Participants Experiencing Clinically Significant Vital Sign Abnormalities [ Time Frame: From first dose up to approximately 49 months ]
  The percent of participants with clinically significant vital sign abnormalities including weight, temperature, blood pressure, pulse rate, and respiratory rate.
• The Percentage of Participants Experiencing Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: From first dose up to approximately 49 months ]
  The percent of participants with clinically significant ECG abnormalities. 12-lead ECG was assessed by a physician trained in ECG interpretation. Intervals including PR, QRS, QT and RR were collected, as well as heart rate and rhythm.
• Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) [ Time Frame: From baseline to cycle 2 day 1 (up to approximately 1 month) ]
  The change from baseline in the EORTC QLQ-C30 questionnaire. The 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. A change of at least 10 points on the standardized domain scores was required for it to be considered meaningful. Results obtained just prior to the start of study treatment on Day 1 of Cycle 1 will serve as the baseline values. If not available, the most recent screening results prior to the start of study treatment on Day 1 of Cycle 1 will be considered the baseline values.
• Change From Baseline in EQ-5D-5L Health Utility Index [ Time Frame: From baseline up to cycle 2 day 1 (up to approximately 1 month) ]
  The EQ-5D is a standardized instrument for use as a measure of health outcome. The descriptive system comprises 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 from the 5 dimensions are coded so that a '1' indicates no problem on that dimension, and '5' indicates the most serious problem. Results obtained just prior to the start of study treatment on Day 1 of Cycle 1 will serve as the baseline values. If not available, the most recent screening results prior to the start of study treatment on Day 1 of Cycle 1 will be considered the baseline values. The responses for the 5 dimensions can be combined in a 5-digit number describing the respondent's health state. Score was converted to a single index value using the cross-walk method to the EQ-5D-3L value set.

Original Secondary Outcome Measures (submitted: October 14, 2015)

• Overall response rate [ Time Frame: Up to approximatly 28 months ]
  The 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 [ Time Frame: Up to approximatly 28 months ]
  Time from randomization to documented morphologic relapse, PD according to modified International Working Group (IWG) Acute myeloid leukemia (AML) response criteria or death from any cause, whichever occurs first
• Duration of response [ Time Frame: Up to approximatly 28 months ]
  Time from the first documented MLFS/CR/CRi/CRp/PR to documented morphologic relapse, Progressive disease (PD) according to modified IWG AML response criteria or death due to any cause, whichever occurs first
• Time to response [ Time Frame: Up to approximatly 28 months ]
  Time from randomization to first documented MLFS/CR/CRi/CRp/PR according to modified IWG AML response criteria
• Treatment mortality at 30 and 60 days [ Time Frame: At 30 and 60 days after treatment start ]
  Rate of death from any cause within 30 and 60 days of initiation of study treatment
• One-year survival [ Time Frame: Up to approximatly 28 months ]
  The probability of survival at 1 year from randomization
• Overall remission rate [ Time Frame: Up to approximatly 28 months ]
  Rate of CR + CRi + CRp according to modified IWG AML response criteria
• Complete remission rate [ Time Frame: Up to approximatly 28 months ]
  Rate of CR according to modified IWG AML response criteria
• Hematologic improvement rate [ Time Frame: Up to approximatly 28 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
• Rate of Hematopoietic stem cell transplantation (HSCT) [ Time Frame: Up to approximatly 28 months ]
  Rate of bridge-to-HSCT through study treatment
• Time to treatment failure [ Time Frame: Up to approximatly 28 months ]
  Time from randomization to discontinuation of study treatment due to any cause response criteria or death due to any cause, whichever occurs first
• Adverse Events (AEs) [ Time Frame: Up to approximatly 28 months ]
  Number of participants with adverse events
• European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Up to approximatly 28 months ]
  A validated quality of life measure applicable to subjects with any cancer diagnosis. .
• EuroQoL Group EQ-5D-5L Health Questionnaire [ Time Frame: Up to approximatly 28 months ]
  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: An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
• Official Title: A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
• Brief Summary: This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.

Detailed Description

Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of patients with AML.

The outcome of first line chemotherapy treatment is poor and many patients fail to attain complete remission (CR, ie refractory) or will eventually relapse. There is no single standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a great need for new therapies.

Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML. AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed or refractory AML.

The study purpose is to test the safety and efficacy of AG-221 compared with conventional care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC, low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late stage AML refractory to or relapsed after second or third line therapy and positive for the IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78 months which includes 42 months enrollment, approximately 7 months treatment and a follow-up period.

Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment response. Bone marrow, blood, cheek swab samples will be used for genetic tests.

This study is being sponsored by Celgene Corporation. Approximately 316 participants will take part in the study.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Leukemia, Myeloid
• Isocitrate Dehydrogenase

Intervention

• Drug: AG-221
  Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days
• Other: BSC
  Best supportive care includes, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support
• Drug: Azacitidine
  continuous 28-day cycles of azacitidine 75 mg/m2/day SC for 7 days, plus BSC
• Drug: Low-dose cytarabine (LDAC)
  continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC
• Drug: Intermediate-dose cytarabine (IDAC)
  28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after IDAC therapy concludes per standard institutional practice

Study Arms

• Experimental: AG-221 plus Best supportive care (BSC)
  Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.
  Interventions:

  • Drug: AG-221
  • Other: BSC
• Active Comparator: Conventional care regimen (CCR)
  Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.
  Interventions:

  • Other: BSC
  • Drug: Azacitidine
  • Drug: Low-dose cytarabine (LDAC)
  • Drug: Intermediate-dose cytarabine (IDAC)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: February 25, 2020): 319
• Original Estimated Enrollment (submitted: October 14, 2015): 280
• Estimated Study Completion Date: December 31, 2023
• Actual Primary Completion Date: March 17, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is ≥ 60 years of age at the time of signing the ICF
2. Subject has primary (ie, de novo) or secondary (progression of MDS or myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO classification (Appendix B)
3. Subject has received second- or third-line of AML therapy (see Appendix G for the definition of prior AML line; note that, for subjects having AML secondary to prior higher risk [Intermediate-2 or High risk according to the International Prognostic Scoring System] MDS treated with a hypomethylating agent [eg, azacitidine or decitabine], the hypomethylating therapy can be counted as a line if there is disease progression to AML during or shortly [eg, within 60 days] after the hypomethylating therapy.)

4. Subject has the following disease status:

   1. Refractory to or relapsed after second- or third-line of intensive therapy for AML (eg, the "7 + 3" regimen):

      at least 5% leukemic blasts in bone marrow (the minimum number of treatment cycles of the intensive therapy is per the investigator's discretion); or

   2. Refractory to or relapsed after second- or third-line low-intensity AML therapy (eg, LDAC, azacitidine or decitabine):

   at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles

5. Subject is eligible for and willing to receive the pre-selected CCR treatment option, according to the investigator's assessment (Note: Subjects with degenerative and toxic encephalopathies, especially after the use of methotrexate or treatment with ionizing radiation, should not receive cytarabine.)
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D)
7. Subject has IDH2 gene mutations tested centrally (using the "investigational use only"PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral blood. (Note: in the event that the central laboratory result is delayed and precludes acute clinical management of a subject who has confirmed IDH2 gene mutation by local evaluation, the subject may be eligible for randomization with approval by the Medical Monitor.)

8. Subject has adequate organ function defined as:

   • Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3 x upper limit of normal (ULN), unless considered due to leukemic organ involvement, following review by the Medical Monitor; and
   • Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome (eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review by the Medical Monitor; and
   • Creatinine clearance > 30 mL/min based on the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR):

   GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 if female) × (1.212 if African American)

9. Females of childbearing potential (FCBP)* may participate, providing they meet the following conditions:

   • Agree to practice true abstinence from sexual intercourse or to use highly effective contraceptive methods (eg, combined [containing estrogen and progestogen] or progestogen-only associated with inhibition of ovulation, oral, injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or male partner sterilization [note that vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the FCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success]) at screening and throughout the study, and for 4 months following the last study treatment (6 months following the last dose of cytarabine); and
   • Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
   • Have a negative serum or urine (investigator's discretion under local regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the start of study treatment in the Treatment Phase (note that the screening serum pregnancy test can be used as the test prior to the start of study treatment in the Treatment Phase if it is performed within the 72-hour timeframe).
10. Male subjects must agree to practice true abstinence from sexual intercourse or to the use of highly effective contraceptive methods (as described above) with non-pregnant female partners of childbearing potential at screening and throughout the course of the study, and should avoid conception with their partners during the course of the study and for 4 months following the last study treatment (6 months following the last dose of cytarabine; 6 months following the last dose of azacitidine in Canada)
11. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
12. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
2. Subject has AML secondary to chronic myelogenous leukemia
3. Subject has received a targeted agent against an IDH2 mutation
4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the start of study treatment. Note that hydroxyurea is allowed prior to the start of study treatment for the control of leukocytosis (however, hydroxyurea should not be given within 72 hours prior to and after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment
6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior therapies
8. Subject 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.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
10. Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
11. Subject has significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment

12. Subject has prior history of malignancy, other than MDS, MPN or AML, 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 are allowed:

    • Basal or squamous cell carcinoma of the skin
    • Carcinoma in situ of the cervix
    • Carcinoma in situ of the breast
    • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis clinical staging system)
13. Subject is known seropositive or active infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
16. Subject is a pregnant or lactating female
17. Subject has known or suspected to have hypersensitivity to any of the components of study treatment
18. Subject is taking those medications (listed in Section 8.2) that are known to prolong QT interval unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment
19. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome) at screening
20. Subject is taking the following sensitive CYP substrate medications that have a narrow therapeutic range are excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)
21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive substrate rosuvastatin should be excluded from the study unless the subject can be transferred to other medications at least 5 half-lives prior to the start of study treatment
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
24. Subject has any condition that confounds the ability to interpret data from the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 60 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, Austria, Brazil, Canada, China, Czechia, Denmark, France, Germany, Italy, Korea, Republic of, Russian Federation, Spain, Taiwan, Turkey, United Kingdom, United States
• Removed Location Countries: Belgium, Czech Republic

Administrative Information

• NCT Number: NCT02577406
• Other Study ID Numbers: AG-221-AML-004
• 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: May 2023