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

NCT02677922 | Active Not Recruiting Phase 1 Results DMC

• 2 other identifiers: AG-221-AML-0052015-003951-23
• Study Type: interventional
• Target: 130
• Locations: 14 countries
• Sites: 49

Brief Summary

The purpose of this study are

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

Conditions

Leukemia, Myeloid, Acute

Keywords

Acute Myeloid Leukemia; Leukemia; Azacitidine; AG-120; AG-221

Outcome Measures

Primary Outcomes (3)

• The Number of Participants Experiencing Dose-limiting Toxicities (DLTs): Phase 1B (Dose Finding Stage)

  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.

  From first dose to 28 days after first dose

• The Number of Participants Experiencing Adverse Events: Phase 1B (Dose Finding and Expansion Stage)

  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.

  From first dose to 28 days after last dose (up to approximately 13 months)

• Overall Response Rate: Phase 2 (Randomized Stage)

  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).

  From first dose up to approximately 26 months

Secondary Outcomes (24)

• Overall Response Rate: Phase 1B (Dose Finding and Expansion Stage)

  From first dose up to approximately 13 months

• Sponsor Derived CR and CRh: Phase 1B (Dose Finding and Expansion Stage)

  From first dose up to approximately 13 months

• Event-free Survival (EFS): Phase 2 (Randomized Stage)

  From randomization to the date of documented relapse, progression, or death due to any cause, whichever occurs first (up to approximately 26 months)

• The Number of Participants Experiencing Adverse Events: Phase 2 (Randomized Stage)

  From first dose to 28 days after last dose (up to approximately 26 months)

• Complete Remission Rate: Phase 2 (Randomized Stage)

  From first dose up to approximately 26 months

Study Arms (3)

AG-120 + Azacitidine

EXPERIMENTAL

Drug: AG-120; Drug: Azacitidine

AG-221 + Azacitidine

EXPERIMENTAL

Drug: Azacitidine; Drug: AG-221

Azacitidine

EXPERIMENTAL

Drug: Azacitidine

Interventions

AG-120 DRUG

Specified dose on specified days

AG-120 + Azacitidine

Azacitidine DRUG

Specified dose on specified days

AG-120 + Azacitidine; AG-221 + Azacitidine; Azacitidine

AG-221 DRUG

Specified dose on specified days

AG-221 + Azacitidine

Eligibility Criteria

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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Celgene: lead

Study Sites (49)

Local Institution - 105

Duarte, California, 91010-301, United States

Location

Local Institution - 107

New Haven, Connecticut, 06510, United States

Location

Local Institution - 108

Chicago, Illinois, 60611, United States

Location

Local Institution - 103

Chicago, Illinois, 60637, United States

Location

Local Institution - 102

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Local Institution - 902

Boston, Massachusetts, 02115, United States

Location

Local Institution - 106

New York, New York, 10065, United States

Location

Local Institution - 110

Dallas, Texas, 75390-85520, United States

Location

Local Institution - 178

Adelaide, South Australia, SA 5000, Australia

Location

Local Institution - 175

Melbourne, 3141, Australia

Location

Local Institution - 177

Perth, 6000, Australia

Location

Local Institution - UNK-121

Yvoir, 5530, Belgium

Location

Local Institution - 125

Toronto, Ontario, M5G 2M9, Canada

Location

Local Institution - 205

Lille, 59037, France

Location

Local Institution - 206

Marseille, 13273, France

Location

Local Institution - 200

Paris, 75475, France

Location

Local Institution - 204

Pessac, 33604, France

Location

Local Institution - 202

Pierre-Bénite, 69495, France

Location

Local Institution - 203

Toulouse, 31059, France

Location

Local Institution - 201

Villejuif, 94805, France

Location

Local Institution - 227

Berlin, 12200, Germany

Location

Local Institution - 230

Dresden, 01307, Germany

Location

Local Institution - 225

Ulm, 89081, Germany

Location

Local Institution - 253

Bologna, Emilia-Romagna, 40138, Italy

Location

Local Institution - 252

Florence, 50134, Italy

Location

Local Institution - 256

Genova, 16132, Italy

Location

Local Institution - 251

Orbassano, 10043, Italy

Location

Local Institution - 254

Padua, 35128, Italy

Location

Local Institution - 250

Pesaro, 31122, Italy

Location

Local Institution - 255

Roma, 00189, Italy

Location

Local Institution - 277

Utrecht, 3584 CX, Netherlands

Location

Local Institution - 327

Lisbon, 1169-050, Portugal

Location

Local Institution - 351

Seoul, 135-710, South Korea

Location

Local Institution - 350

Seoul, 138-736, South Korea

Location

Local Institution - 379

Barcelona, 08036, Spain

Location

Local Institution - 375

Barcelona, 08907, Spain

Location

Local Institution - 376

Cáceres, 10005, Spain

Location

Local Institution - 378

Madrid, 28007, Spain

Location

Local Institution - 381

Madrid, 28033, Spain

Location

Local Institution - 380

Málaga, 29010, Spain

Location

Local Institution - 377

Valencia, 46009, Spain

Location

Local Institution - UNK-52

Gothenburg, 413 45, Sweden

Location

Local Institution - 403

Basel, 4031, Switzerland

Location

Local Institution - 401

Zurich, 0, Switzerland

Location

Local Institution - 429

Birmingham, B15 2TH, United Kingdom

Location

Local Institution - 427

Headington, OX3 9DU, United Kingdom

Location

Local Institution - 428

London, SE5 9RS, United Kingdom

Location

Local Institution - 430

Sutton (Surrey), SM2 5PT, United Kingdom

Location

Related Publications (4)

• 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

• Woods A, Norsworthy KJ, Wang X, Vallejo J, Chiu Yuen Chow E, Li RJ, Sun J, Charlab R, Jiang X, Pazdur R, Theoret MR, de Claro RA. FDA Approval Summary: Ivosidenib in Combination with Azacitidine for Treatment of Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation. Clin Cancer Res. 2024 Apr 1;30(7):1226-1231. doi: 10.1158/1078-0432.CCR-23-2234.

  PMID: 38010220 DERIVED

• 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.

  PMID: 34672961 DERIVED

• 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.

  PMID: 33119479 DERIVED

Related Links

• BMS Clinical Trial Information

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

ivosidenib; Azacitidine; enasidenib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; 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

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 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2016
• First Posted: February 9, 2016
• Study Start: June 3, 2016
• Primary Completion: August 2, 2018
• Study Completion (Estimated): September 30, 2026
• Last Updated: February 19, 2026
• Results First Posted: November 22, 2022

Record last verified: 2026-02

Locations

PT (1); CA (1); DE (3); NL (1); AU (3); ES (7); SE (1); CH (2); US (9); KR (2); GB (4); FR (7); IT (7); BE (1)