Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Participants With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation

NCT ID: NCT03173248

Last Updated: 2025-11-10

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 146 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-26
• Study Completion Date: 2026-06-30

Brief Summary

Study AG120-C-009 is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of AG-120 (ivosidenib) + azacitidine vs placebo + azacitidine in adult participants with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy. The primary endpoint is event-free survival (EFS). The key secondary efficacy endpoints are overall survival (OS), rate of complete remission (CR), rate of CR and complete remission with partial hematologic recovery (CRh), and overall response rate (ORR). Participants eligible for study treatment based on Screening assessments will be randomized 1:1 to receive oral AG-120 or matched placebo, both administered in combination with subcutaneous (SC) or intravenous (IV) azacitidine. An estimated 200 participants will take part in the study.

Conditions

Newly Diagnosed Acute Myeloid Leukemia (AML); Untreated AML; AML Arising From Myelodysplastic Syndrome (MDS); Leukemia, Myeloid, Acute

Keywords

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

AG-120 + Azacitidine

Participants received AG-120 500 mg orally, once daily (QD) in combination with azacitidine 75 milligrams per square meter per day (mg/m\^2/day) subcutaneously (SC) or intravenously (IV), on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation.

Group Type: EXPERIMENTAL

AG-120

Intervention Type: DRUG

Tablets administered orally

Azacitidine

Intervention Type: DRUG

Administered SC or IV

Placebo + Azacitidine

Participants received AG-120 matching placebo orally, QD in combination with azacitidine 75 mg/m\^2/day SC or IV, on Days 1-7, or on Days 1-5 and 8-9, of each 28-day cycle for a minimum of 6 cycles until death, disease relapse, disease progression, development of unacceptable toxicity (adverse event), confirmed pregnancy, withdrawal by participant or protocol violation .

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Tablets administered orally

Azacitidine

Intervention Type: DRUG

Administered SC or IV

Interventions

AG-120

Tablets administered orally

Intervention Type: DRUG

Placebo

Tablets administered orally

Intervention Type: DRUG

Azacitidine

Administered SC or IV

Intervention Type: DRUG

Other Intervention Names

Ivosidenib; Vidaza®

Eligibility Criteria

Inclusion Criteria

1. Be ≥ 18 years of age and meet at least 1 of the following criteria defining ineligibility for intensive induction chemotherapy (IC): ≥ 75 years old, Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 2, severe cardiac disorder (e.g., congestive heart failure requiring treatment, left ventricular ejection fraction (LVEF), ≤50%, or chronic stable angina), severe pulmonary disorder (e.g., diffusing capacity of the lungs for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%), creatinine clearance <45 mL/minute, bilirubin >1.5 times the upper limit of normal (ULN) and/or have any other comorbidity that the Investigator judges to be incompatible with intensive IC and must be reviewed and approved by the Medical Monitor before study enrollment.

2. Have previously untreated AML, defined according to World Health Organization (WHO) criteria, with ≥ 20% leukemic blasts in the bone marrow. Participants with extramedullary disease alone (i.e., no detectable bone marrow and no detectable peripheral blood AML) are not eligible for the study.

3. Have an isocitrate dehydrogenase 1 (IDH1) mutation.

4. Have an ECOG PS score of 0 to 2.

5. Have adequate hepatic function.

6. Have adequate renal function.

7. Have agreed to undergo serial blood and bone marrow sampling.

8. Be able to understand and willing to sign an informed consent form (ICF).

9. Be willing to complete Quality of Life assessments during the study

10. If female with reproductive potential, must have a negative serum pregnancy test prior to the start of study therapy. Females of reproductive potential, as well as fertile men and their female partners of reproductive potential, must agree to use 2 effective forms of contraception.

Exclusion Criteria

1. Are candidates for and willing to receive intensive induction chemotherapy (IC) for their AML.

2. Have received any prior treatment for AML with the exception of hydroxyurea.

3. Have received a hypomethylating agent for myelodysplastic syndrome (MDS).

4. Participants who had previously received an experimental agent for MDS may not be randomized until a washout period has elapsed since the last dose of that agent.

5. Have received prior treatment with an IDH1 inhibitor.

6. Have a known hypersensitivity to any of the components of AG-120, matched placebo, or azacitidine.

7. Are female and pregnant or breastfeeding.

8. Have an active, uncontrolled, systemic fungal, bacterial, or viral infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment.

9. Have a prior history of cancer other than MDS or myeloproliferative disorder, unless the participant has been free of the disease for ≥ 1 year prior to the start of study treatment.

10. Have had significant active cardiac disease within 6 months prior to the start of the study treatment.

11. Have any condition that increases the risk of abnormal ECG or cardiac arrhythmia.

12. Have a condition that limits the ingestion or absorption of drugs administered by mouth.

13. Have uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or diastolic BP > 100 mmHg).

14. Have clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia.

15. Have immediate, life-threatening, severe complications of leukemia, such as uncontrolled bleeding, pneumonia with hypoxia or sepsis, and/or disseminated intravascular coagulation.

16. Have any other medical or psychological condition deemed by the Investigator to be likely to interfere with the participant's ability to give informed consent or participate in the study.

17. Are taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥5 half-lives prior to dosing, or unless the medications can be properly monitored during the study. (If equivalent medication is not available, heart rate corrected QT interval [QTc] will be closely monitored.)

18. Have a known medical history of progressive multifocal leukoencephalopathy.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut de Recherches Internationales Servier

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Norton Cancer Institute - Suburban

Louisville, Kentucky, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Flinders Medical Centre

Bedford Park, South Australia, Australia

Salzburger Landeskliniken

Salzburg, , Austria

Krankenhaus Hietzing mit Neurologischem Zentrum Rosenhugel

Vienna, , Austria

Unicamp Universidade Estadual de Campinas

Campinas, São Paulo, Brazil

Hospital Amaral Carvalho

Jaú, São Paulo, Brazil

Instituto Nacional de Cancer

Rio de Janeiro, , Brazil

Hospital Sirio Libanes

São Paulo, , Brazil

Hospital Sao Jose

São Paulo, , Brazil

Hospital Santa Marcelina

São Paulo, , Brazil

Cancer Care Manitoba

Winnipeg, Manitoba, Canada

University Health Network

Toronto, Ontario, Canada

Henan Cancer Hospital

Zhengzhou, Henan, China

West China Hospital Sichuan University

Chengdu, Sichuan, China

Peking Union Medical College Hospital

Beijing, , China

Guangdong Provincial People's Hospital

Guangzhou, , China

The First Affiliated Hospital, College of Medicine, Zhejiang University

Hangzhou, , China

Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences

Tianjin, , China

Fakultni nemocnice Ostrava

Ostrava, , Czechia

Hopital Haut Leveque

Pessac, Gironde, France

Hopital Bretonneau

Tours, Indre-et-Loire, France

Hotel Dieu - Nantes

Nantes, Loire-Atlantique, France

Centre Hospitalier Lyon Sud

Pierre-Bénite, Rhone, France

Centre Hospitalier Le Mans

Le Mans, Sarthe, France

CHRU de Brest - Hopital Morvan

Brest, , France

Institut dHematologie de Basse Normandie

Caen, , France

CHU de Grenoble

Grenoble, , France

Centre Hospitalier de Versailles CHV Hopital Andre Mignot

Le Chesnay, , France

Groupe Hospitalier Necker Enfants Malades

Paris, , France

CHRU de Poitiers La Miletrie

Poitiers, , France

Hopital de Hautepierre

Strasbourg, , France

EDOG - Institut Claudius Regaud - PPDS

Toulouse, , France

Institut Gustave Roussy

Villejuif, , France

Universitatsklinikum Essen

Essen, North Rhine-Westphalia, Germany

Klinikum Chemnitz gGmbH

Chemnitz, Saxony, Germany

Charite - Universitatsmedizin Berlin

Berlin, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Universitatsklinikum Leipzig

Leipzig, , Germany

LMU Klinikum der Universitat Munchen

München, , Germany

Universitatsklinikum Ulm

Ulm, , Germany

Rabin Medical Center - PPDS

Petah Tikva, , Israel

Kaplan Medical Center

Rehovot, , Israel

Shamir Medical Center Assaf Harofeh

Tzrifin, , Israel

ASST dei Sette Laghi - Ospedale Di Circolo E Fondazione Macchi

Varese, Lombardy, Italy

Istituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori IRST - PPDS

Meldola, , Italy

Ospedale San Raffaele S.r.l. - PPDS

Milan, , Italy

ASST Grande Ospedale Metropolitano Niguarda - Presidio Ospedaliero Ospedale Niguarda Ca' Granda

Milan, , Italy

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, , Italy

Ospedale Infermi di Rimini

Rimini, , Italy

Azienda Ospedaliera Citta della Salute e della Scienza di Torino

Torino, , Italy

Matsuyama Red Cross Hospital

Matsuyama, Ehime, Japan

University of Fukui Hospital

Fukui, , Japan

Japanese Red Cross Society Himeji Hospital

Himeji, , Japan

Kobe City Medical Center General Hospital

Kobe, , Japan

SINACOR

Culiacán, , Mexico

Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran

México, , Mexico

VU Medisch Centrum

Amsterdam, North Holland, Netherlands

Universitair Medisch Centrum Groningen

Nijmegen, , Netherlands

Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu

Wroclaw, Lower Silesian Voivodeship, Poland

Instytut Hematologii i Transfuzjologii

Warsaw, Masovian Voivodeship, Poland

Uniwersyteckie Centrum Kliniczne

Gdansk, , Poland

Kaluga Regional Clinical Hospital

Kaluga, , Russia

City Clinical Hospital # 40

Moscow, , Russia

National Cancer Center

Goyang-si, Gyeonggido, South Korea

Ajou University Hospital

Suwon, Gyeonggido, South Korea

Pusan National University Hospital

Busan, , South Korea

Severance Hospital Yonsei University Health System

Seoul, , South Korea

Seoul National University Hospital

Seoul, , South Korea

CHUS H. Clinico U. de Santiago

Santiago de Compostela, A Coruna, Spain

Hospital Universitario Son Espases

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitario Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital Universitario de Gran Canaria Doctor Negrin

Las Palmas de Gran Canaria, Las Palmas, Spain

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, , Spain

Hospital Clinic de Barcelona

Barcelona, , Spain

Hospital General Universitario Gregorio Maranon

Madrid, , Spain

Hospital Universitario Ramon y Cajal

Madrid, , Spain

Hospital Universitario Fundacion Jimenez Diaz

Madrid, , Spain

Hospital Universitario 12 de Octubre

Madrid, , Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, , Spain

Hospital Universitari i Politecnic La Fe de Valencia

Valencia, , Spain

Hospital Clinico Universitario Lozano Blesa

Zaragoza, , Spain

Changhua Christian Medical Foundation Changhua Christian Hospital

Changhua, , Taiwan

Kaohsiung Medical University Hospital

Kaohsiung City, , Taiwan

China Medical University Hospital

Taichung, , Taiwan

Chi Mei Medical Center, Liouying

Tainan, , Taiwan

National Taiwan University Hospital

Taipei, , Taiwan

Birmingham Heartlands Hospital

Birmingham, West Midlands, United Kingdom

Countries

United States; Australia; Austria; Brazil; Canada; China; Czechia; France; Germany; Israel; Italy; Japan; Mexico; Netherlands; Poland; Russia; South Korea; Spain; Taiwan; United Kingdom

References

Montesinos P, Recher C, Vives S, Zarzycka E, Wang J, Bertani G, Heuser M, Calado RT, Schuh AC, Yeh SP, Daigle SR, Hui J, Pandya SS, Gianolio DA, de Botton S, Dohner H. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519-1531. doi: 10.1056/NEJMoa2117344.

Reference Type: BACKGROUND

PMID: 35443108 (View on PubMed)

Montesinos P, Marchione DM, Recher C, Heuser M, Vives S, Zarzycka E, Wang J, Riva M, Calado RT, Schuh AC, Yeh SP, Tron AE, Hui J, Gianolio DA, Choe S, Patel P, De Botton S, DiNardo CD, Dohner H. Long-term results from the AGILE study of azacitidine plus ivosidenib vs placebo in newly diagnosed IDH1-mutated AML. Blood Adv. 2025 Oct 28;9(20):5177-5189. doi: 10.1182/bloodadvances.2025016399.

Reference Type: DERIVED

PMID: 40706052 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38010220 (View on PubMed)

Provided Documents

Document Type: Study Protocol

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Document Type: Statistical Analysis Plan

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Study Documents

Document Type: Individual Participant Data Set

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Document Type: Study Protocol

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Document Type: Statistical Analysis Plan

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Document Type: Informed Consent Form

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Document Type: Clinical Study Report

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Document Type: Study-level clinical trial data

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Other Identifiers

AG120-C-009

Identifier Type: -

Identifier Source: org_study_id