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

NCT02577406 | Completed Phase 3 Results DMC

• 1 other identifier: AG-221-AML-004
• Study Type: interventional
• Target: 319
• Locations: 17 countries
• Sites: 92

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.

Conditions

Leukemia, Myeloid; Isocitrate Dehydrogenase

Keywords

AG-221; CC-90007; Efficacy; Safety; Leukemia; Acute myeloid meukemia; Isocitrate dehydrogenase 2 mutation; Enasidenib

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS)

  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.

  From randomization to death due to any cause (up to approximately 49 months)

Secondary Outcomes (19)

• Overall Response Rate

  From randomization up to study completion (approximately 78 months)

• Event-Free Survival

  From randomization up to study completion (approximately 78 months)

• Duration of Response

  From randomization up to study completion (approximately 78 months)

• Time to Response

  From randomization to to first documented MLFS/CR/CRi/CRp/PR (up to approximately 49 months)

• Treatment Mortality at 30 Days

  From first dose to 30 days after first dose

Study Arms (2)

AG-221 plus Best supportive care (BSC)

EXPERIMENTAL

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

Drug: AG-221; Other: BSC

Conventional care regimen (CCR)

ACTIVE COMPARATOR

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.

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

Interventions

AG-221 DRUG

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

AG-221 plus Best supportive care (BSC)

BSC OTHER

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

AG-221 plus Best supportive care (BSC); Conventional care regimen (CCR)

Azacitidine DRUG

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

Conventional care regimen (CCR)

Low-dose cytarabine (LDAC) DRUG

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

Conventional care regimen (CCR)

Intermediate-dose cytarabine (IDAC) DRUG

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

Conventional care regimen (CCR)

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

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

Sponsors & Collaborators

• Celgene: lead

Study Sites (93)

Local Institution - 121

Miami, Florida, 33136, United States

Location

University of Florida Health Cancer Center at Orlando Health

Orlando, Florida, 32806, United States

Location

Local Institution - 111

Chicago, Illinois, 60637, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Local Institution - 128

New York, New York, 10029, United States

Location

Strong Health System

Rochester, New York, 14642, United States

Location

Montefiore Medical Center Albert Einstein Cancer Center

The Bronx, New York, 10467, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

Local Institution - 104

Greenville, South Carolina, 29615, United States

Location

Baylor Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Local Institution - 901

Concord, New South Wales, 2139, Australia

Location

Local Institution - 904

Adelaide, South Australia, 5000, Australia

Location

Local Institution - 906

East Melbourne, 3002, Australia

Location

Local Institution - 905

Melbourne, 3004, Australia

Location

Local Institution - 803

Linz, 4020, Austria

Location

Local Institution - 811

Yvoir, 5530, Belgium

Location

Local Institution - 250

Porto Alegre, Rio Grande do Sul, 90020-090, Brazil

Location

Local Institution - 252

Porto Alegre, RS, Rio Grande do Sul, 90035-003, Brazil

Location

Local Institution - 251

Jaú, 17210-080, Brazil

Location

Local Institution - 253

Rio de Janeiro, 20211-030, Brazil

Location

Local Institution - 254

São Paulo, 01308-050, Brazil

Location

Local Institution - 202

Edmonton, Alberta, T6G2V2, Canada

Location

Local Institution - 203

Winnipeg, Manitoba, R3E OV9, Canada

Location

Local Institution - 201

Toronto, Ontario, M5G 2M9, Canada

Location

Local Institution - 204

Montreal, Quebec, H3A 1A1, Canada

Location

Local Institution - 885

Beijing, 100080, China

Location

Local Institution - 884

Beijing, 100191, China

Location

Local Institution - 892

Beijing, 100853, China

Location

Local Institution - 888

Chengdu, Sichuan, 610041, China

Location

Local Institution - 882

Fuzhou, 350001, China

Location

Local Institution - 881

Guangzhou, Guangdong, 510080, China

Location

Local Institution - 883

Hangzhou, 310006, China

Location

Local Institution - 887

Shanghai, 200025, China

Location

Local Institution - 891

Shanghai, 200433, China

Location

Local Institution - 889

Zhengzhou, 0, China

Location

Local Institution - 822

Prague, 128 08, Czechia

Location

Local Institution - 834

Aalborg, DK-9000, Denmark

Location

Local Institution - 833

Arhus C, DK-8000, Denmark

Location

Local Institution - 831

Copenhagen, 2100, Denmark

Location

Local Institution - 832

Odense, DK-5000, Denmark

Location

Local Institution - 606

Angers, 49033, France

Location

Local Institution - 605

Bobigny, 93009, France

Location

Local Institution - 602

Lille, 59037, France

Location

Local Institution - 612

Marseille, 13273, France

Location

Local Institution - 601

Nantes, 44093, France

Location

Local Institution - 607

Pessac, 33604, France

Location

Local Institution - 611

Pierre-Bénite, 69495, France

Location

Local Institution - 609

Toulouse, 31009, France

Location

Local Institution - 610

Versailles, 78000, France

Location

Local Institution - 604

Villejuif, 94805, France

Location

Local Institution - 403

Dresden, D-01307, Germany

Location

Local Institution - 413

Essen, 45122, Germany

Location

Local Institution - 406

Frankfurt, 60590, Germany

Location

Local Institution - 401

Hanover, 30625, Germany

Location

Local Institution - 412

Leipzig, 04103, Germany

Location

Local Institution - 402

Mainz, 55131, Germany

Location

Local Institution - 409

München, 81377, Germany

Location

Local Institution - 407

Ulm, 89081, Germany

Location

Local Institution - 305

Bologna, 40138, Italy

Location

Local Institution - 304

Brescia, 25123, Italy

Location

Local Institution - 302

Florence, 50139, Italy

Location

Local Institution - 301

Naples, 80131, Italy

Location

Local Institution - 306

Palermo, 90146, Italy

Location

Local Institution - 303

Reggio Calabria, 89100, Italy

Location

Local Institution - 307

Roma, 00133, Italy

Location

Local Institution - 861

Krasnoyarsk, 660022, Russia

Location

Local Institution - 864

Moscow, 123182, Russia

Location

Local Institution - 863

Moscow, 129301, Russia

Location

Local Institution - 862

Saint Petersburg, 191024, Russia

Location

Local Institution - 953

Hwasun-gun, 519-809, South Korea

Location

Local Institution - 952

Seoul, 137-701, South Korea

Location

Local Institution - 701

Oviedo, Principality of Asturias, 33011, Spain

Location

Local Institution - 706

Avda, Campanar 21, 46009, Spain

Location

Local Institution - 708

Barcelona, 08035, Spain

Location

Local Institution - 704

Barcelona, 8036, Spain

Location

Local Institution - 709

Salamanca, 37007, Spain

Location

Local Institution - 702

Seville, 41013, Spain

Location

Local Institution - 942

Taichung, Northern Dist., 404, Taiwan

Location

Local Institution - 940

Taipei, Zhongzheng Dist., 10002, Taiwan

Location

Local Institution - 941

Taoyuan District, 333, Taiwan

Location

Local Institution - 873

Ankara, 06100, Turkey (Türkiye)

Location

Local Institution - 872

Ankara, 06200, Turkey (Türkiye)

Location

Local Institution - 871

Ankara, 6500, Turkey (Türkiye)

Location

Local Institution - 874

Denizli, 20070, Turkey (Türkiye)

Location

Local Institution - 875

Gaziantep, 27310, Turkey (Türkiye)

Location

Local Institution - 503

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

Local Institution - 501

London, EC1A 7BE, United Kingdom

Location

Local Institution - 507

London, SE5 9RS, United Kingdom

Location

Local Institution - 502

Manchester Withington, M20 4BX, United Kingdom

Location

Local Institution - 510

Oxford, OX3 9DU, United Kingdom

Location

Local Institution - 509

Sutton (Surrey), SM2 5PT, United Kingdom

Location

Related Publications (1)

• Montesinos P, Fathi AT, de Botton S, Stein EM, Zeidan AM, Zhu Y, Prebet T, Vigil CE, Bluemmert I, Yu X, DiNardo CD. Differentiation syndrome associated with treatment with IDH2 inhibitor enasidenib: pooled analysis from clinical trials. Blood Adv. 2024 May 28;8(10):2509-2519. doi: 10.1182/bloodadvances.2023011914.

  PMID: 38507688 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Leukemia, Myeloid; Leukemia

Interventions

enasidenib; Azacitidine; Cytarabine

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Arabinonucleosides

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please Email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 14, 2015
• First Posted: October 16, 2015
• Study Start: December 30, 2015
• Primary Completion: March 17, 2020
• Study Completion: March 25, 2024
• Last Updated: May 18, 2025
• Results First Posted: September 10, 2022

Record last verified: 2025-05

Locations

US (12); CA (4); TU (5); AU (4); GB (6); IT (7); CZ (1); RU (4); KR (2); ES (6); BR (5); FR (10); CN (10); BE (1); DK (4); TW (3); DE (8)