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Enzyme Inhibitors

Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.

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.

Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days

AG-221

Best supportive care includes, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support

continuous 28-day cycles of azacitidine 75 mg/m2/day SC for 7 days, plus BSC

continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC

Low-dose cytarabine (LDAC)

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

Intermediate-dose cytarabine (IDAC)

Bristol-Myers Squibb

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.

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.

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

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

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.

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).

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.

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 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).

The number of participant deaths from any cause within 30 days of initiation of study treatment.

The number of participant deaths from any cause within 60 days of initiation of study treatment.

The proportion of participants alive at 1 year after randomization

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.

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.

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 during the study.

Time from randomization to discontinuation of study treatment due to any cause

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 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 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 with clinically significant vital sign abnormalities including weight, temperature, blood pressure, pulse rate, and respiratory rate.

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.

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.

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.

Celgene

Serious Adverse Events and Other (Not Including Serious) Adverse Events were assessed/monitored for the treated population. All-Cause Mortality was assessed for the randomized population.

Participants receive continuous 28-day cycles of AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus best supportive care (BSC).

Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

BSC Only

Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day subcutaneous (SC) for 7 days, plus best supportive care (BSC)

Azacitidine + BSC

Participants receive continuous 28-day cycles of cytarabine 20 mg subcutaneous (SC) twice a day (BID) for 10 days, plus best supportive care (BSC).

LDAC + BSC

Participants receive 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day Intravenously (IV) for 3 to 6 days, per standard institutional practice, plus best supportive care (BSC); only BSC given after intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.

IDAC + BSC

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC: Participants receive 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 intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.

Conventional Care Regimens (CCRs)

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Bristol-Myers Squibb Study Director

Overall Survival (OS)

Treatment options include best supportive care (BSC) only, azacitidine subcutaneous (SC) plus BSC, LDAC subcutaneous (SC) plus BSC, or IDAC intravenously (IV) plus BSC.

BSC only: Participants receive continuous 28-day cycles of best supportive care (BSC). BSC includes, but is not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome associated with therapy of mutant isocitrate dehydrogenase (IDH) inhibition (ie, IDH differentiation syndrome), anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support.

AZA+BSC: Participants receive continuous 28-day cycles of azacitidine 775 mg/m2/day SC for 7 days, plus BSC.

LDAC+BSC: Participants receive continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC.

IDAC+BSC :Participants receive 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 intermediate-dose cytarabine (IDAC) therapy concludes per standard institutional practice.

Overall Response Rate

Event-Free Survival

All participants who achieved CR/CRi/CRp/PR/MLFS

Duration of Response

Time to Response

Treatment Mortality at 30 Days

Treatment Mortality at 60 Days

One-Year Survival Rate

Overall Remission Rate

Complete Remission Rate

Hematologic Improvement Rate

The Number of Participants That Underwent Hematopoietic Stem Cell Transplantation (HSCT)

Time to Treatment Failure

Treatment-Emergent Adverse Event (TEAE)

TEAE Related to Study Drug

Grade ≥ 3 TEAE

Grade ≥ 3 TEAE Related to Study Drug

Serious TEAE

Serious TEAE Related to Study Drug

TEAE Leading to Discontinuation of Study Drug

Treatment-related TEAE Leading to Discontinuation of Study Drug

TEAE Leading to Study Drug Dose Reduction Only

Treatment-related TEAE Leading to Study Drug Dose Reduction Only

TEAE Leading to Study Drug Dose Interruption Only

Treatment-related TEAE Leading to Study Drug Dose Interruption Only

TEAE Leading to Study Drug Dose Reduction or Dose Interruption

Treatment-related TEAE Leading to Study Drug Dose Reduction or Dose Interruption

TEAE Leading to Death

Treatment-related TEAE Leading to Death

The Number of Participants Experiencing Adverse Events (AEs)

The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Serum Chemistry

The Percent of Participants Experiencing Clinically Significant Laboratory Abnormalities - Hematology

The Percent of Participants Experiencing Clinically Significant Vital Sign Abnormalities

All treated participants with evaluable measurements

The Percentage of Participants Experiencing Clinically Significant Electrocardiogram (ECG) Abnormalities

Global QoL

Physical Functioning

Role Functioning

Cognitive Functioning

Emotional Functioning

Social Functioning

Fatigue

Nausea / Vomiting

Pain

Dyspnea

Insomnia

Appetite Loss

Constipation

Diarrhea

Financial Difficulties

All participants who completed at least 15 of the 30 items at baseline and at least one post-baseline assessment based on EORTC QLQ-C30

Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)

All participants with non-missing score of EQ-5D-5L Health Utility Index (i.e. all five items were completed) at baseline

Spots Global Cancer Trial Database for isocitrate dehydrogenase 2 mutation