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

Completed · Phase 3

Conditions studied: Leukemia, Myeloid, Isocitrate Dehydrogenase

In brief

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.

Key facts

Study ID

NCT02577406

Run by

Celgene

People needed

319

Starts

2015-12-30

Expected to finish

2024-03-25

Last updated by the study team

2025-05-18

Who can join

Age: 60 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Subjects must satisfy the following criteria to be enrolled in the study:
• Subject is ≥ 60 years of age at the time of signing the ICF
• 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)
• 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.)
• Subject has the following disease status:
• 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
• 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
• 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.)
• Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D)
• 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.)
• 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)
• 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).
• 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)
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements

You may not qualify if…

• The presence of any of the following will exclude a subject from enrollment:
• Subject is suspected or proven to have acute promyelocytic leukemia based on morphology, immunophenotype, molecular assay, or karyotype
• Subject has AML secondary to chronic myelogenous leukemia
• Subject has received a targeted agent against an IDH2 mutation
• 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).
• Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, whichever is longer, prior to the start of study treatment
• 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.
• Subject has persistent, clinically significant non-hematologic toxicities from prior therapies
• 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.
• 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)
• Subject has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation
• 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
• 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)
• 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)
• Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
• Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg)
• Subject is a pregnant or lactating female
• Subject has known or suspected to have hypersensitivity to any of the components of study treatment
• 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
• 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

Where it is running

• University of Florida Health Cancer Center at Orlando Health — Orlando, Florida, United States
• Local Institution - 111 — Chicago, Illinois, United States
• John Theurer Cancer Center at Hackensack University Medical Center — Hackensack, New Jersey, United States
• Roswell Park Cancer Institute — Buffalo, New York, United States
• Local Institution - 128 — New York, New York, United States
• Strong Health System — Rochester, New York, United States
• Montefiore Medical Center Albert Einstein Cancer Center — The Bronx, New York, United States
• Duke University Medical Center — Durham, North Carolina, United States
• University Hospitals Cleveland Medical Center — Cleveland, Ohio, United States
• Local Institution - 104 — Greenville, South Carolina, United States
• Baylor Sammons Cancer Center — Dallas, Texas, United States
• Local Institution - 901 — Concord, New South Wales, Australia
• Local Institution - 904 — Adelaide, South Australia, Australia
• Local Institution - 906 — East Melbourne, Australia
• Local Institution - 905 — Melbourne, Australia
• Local Institution - 803 — Linz, Austria
• Local Institution - 811 — Yvoir, Belgium
• Local Institution - 250 — Porto Alegre, Rio Grande do Sul, Brazil
• Local Institution - 252 — Porto Alegre, RS, Rio Grande do Sul, Brazil
• Local Institution - 251 — Jaú, Brazil
• Local Institution - 253 — Rio de Janeiro, Brazil
• Local Institution - 254 — São Paulo, Brazil
• Local Institution - 202 — Edmonton, Alberta, Canada
• Local Institution - 203 — Winnipeg, Manitoba, Canada
• Local Institution - 121 — Miami, Florida, United States

Full record on ClinicalTrials.gov

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