Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation

NCT02074839 | Recruiting Phase 1

• 1 other identifier: AG120-C-001
• Study Type: interventional
• Target: 291
• Locations: 2 countries
• Sites: 30

Brief Summary

The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Additionally, the study includes a substudy evaluating the safety and tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome with an IDH1 mutation. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Conditions

Relapsed or Refractory Acute Myeloid Leukemia (AML); Untreated AML; Other IDH1-mutated Positive Hematologic Malignancies; Myelodysplastic Syndromes

Keywords

acute myeloid leukemia; AML; myelodysplastic syndrome; MDS; hematologic malignancies; IDH; Untreated AML; IDH1; relapsed AML; refractory AML

Outcome Measures

Primary Outcomes (5)

• Safety/tolerability: incidence of adverse events.

  up to 26 weeks, on average

• Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies.

  up to 26 weeks, on average

• Assess clinical activity of AG-120 in subjects with relapsed or refractory AML who are enrolled in the Expansion Phase.

  up to 26 weeks, on average

• Safety/tolerability of treatment with AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.

  up to 26 weeks, on average

• Assess clinical activity of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.

  up to 26 weeks, on average

Secondary Outcomes (8)

• Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies.

  up to 26 weeks, on average

• Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies.

  up to 26 weeks, on average

• Pharmacodynamic relationship of AG-120 and 2-HG.

  up to 26 weeks, on average

• Clinical Activity of AG-120 in advanced hematologic malignancies according to the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS or MDS/myeloproliferative neoplasms (MPN).

  up to 26 weeks, on average

• Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Cmax) of AG-120 in subjects with R/R MDS.

  up to 26 weeks, on average

Study Arms (1)

AG-120

EXPERIMENTAL

AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.

Drug: AG-120

Interventions

AG-120 DRUG

AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle. Subjects may continue treatment with AG-120 until disease progression, development of other unacceptable toxicity or hematopoietic stem cell transplant.

AG-120

Eligibility Criteria

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

You may qualify if:

• Subject must be ≥18 years of age.
• Subjects must have documented IDH1 R132 gene-mutated advanced hematologic malignancy based on local or central evaluation.
• Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
• Subjects must have ECOG PS of 0 to 2.
• Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed).
• Subjects must have adequate hepatic function as evidenced by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic disease and serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic disease
• Subjects must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN or creatinine clearance \>40mL/min based on Cockroft-Gault glomerular filtration rate (GFR)
• Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
• Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy and on the first day of study drug administration.

You may not qualify if:

• Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-120, or subjects 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 steroids post HSCT and/or topical for ongoing skin GVHD is permitted.)
• Subjects who received systemic anticancer therapy or radiotherapy \<14 days prior to their first day of study drug administration. (Hydroxyurea is allowed prior to enrollment and after the start of AG-120).
• Subjects who received an investigational agent \<14 days prior to their first day of study drug administration.
• Subjects who are pregnant or breastfeeding.
• Subjects with an active severe infection or with an unexplained fever \>38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
• Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.
• Subjects with a history of myocardial infarction within the last 6 months of screening.
• Subjects with a known unstable or uncontrolled angina pectoris.
• Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
• Subjects with known unstable or uncontrolled angina pectoris.
• Subjects with heart-rate corrected QT (QTc) interval ≥450 ms or other factors that increase the risk of QT prolongation or arrhythmic events.
• Patients taking medications that are known to prolong the QT interval
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
• Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
• Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.

Sponsors & Collaborators

• Institut de Recherches Internationales Servier: lead

Study Sites (30)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

ACTIVE NOT RECRUITING

Mayo Clinic-AZ

Phoenix, Arizona, 85259, United States

TERMINATED

City of Hope

Duarte, California, 91010, United States

ACTIVE NOT RECRUITING

University of California-Los Angeles

Los Angeles, California, 90095, United States

TERMINATED

University of California-San Francisco

San Francisco, California, 94143, United States

TERMINATED

University of Colorado Denver

Aurora, Colorado, 80045, United States

TERMINATED

Mayo Clinic-Jacksonville

Jacksonville, Florida, 32224, United States

TERMINATED

University of Miami

Miami, Florida, 33136, United States

TERMINATED

Moffit Cancer Center

Tampa, Florida, 33612, United States

ACTIVE NOT RECRUITING

Emory University

Atlanta, Georgia, 30322, United States

ACTIVE NOT RECRUITING

Northwestern University Medical Hospital

Chicago, Illinois, 60611, United States

TERMINATED

John Hopkins Cancer Center

Baltimore, Maryland, 21287, United States

ACTIVE NOT RECRUITING

Massachusetts General Hospital

Boston, Massachusetts, 02214, United States

TERMINATED

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

TERMINATED

Karmanos Cancer Center

Detroit, Michigan, 48201, United States

TERMINATED

Washington University

St Louis, Missouri, 63110, United States

TERMINATED

Memorial Sloan Kettering Cancer Center

New York, New York, 10021, United States

ACTIVE NOT RECRUITING

Cornell Cancer Center

New York, New York, 10065, United States

TERMINATED

Duke Cancer Center

Durham, North Carolina, 27705, United States

TERMINATED

Cleveland Clinic

Cleveland, Ohio, 44124, United States

WITHDRAWN

Ohio State University

Columbus, Ohio, 43210, United States

TERMINATED

Oregon Health and Science University

Portland, Oregon, 97239, United States

TERMINATED

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

RECRUITING

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

TERMINATED

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

RECRUITING

MD Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

Hopital La Timone

Marseille, France

TERMINATED

Hopital Haut-Leveque

Pessac, 33600, France

RECRUITING

Central Lyon Sud

Pierre-Bénite, 69310, France

RECRUITING

Institute Gustave Roussly (IGR)

Villejuif, 94800, France

RECRUITING

Related Publications (8)

• Sun M, Yin Q, Liang Y, Chang C, Zheng J, Li J, Ji C, Qiu H, Li J, Gong Y, Luo S, Zhang Y, Chen R, Shen Z, Yue Z, Wang S, Shi Q, Yang J, Jin J, Wang J. Ivosidenib in Chinese patients with relapsed or refractory isocitrate dehydrogenase 1 mutated acute myeloid leukemia: a registry study. Blood Sci. 2024 Jun 20;6(3):e00196. doi: 10.1097/BS9.0000000000000196. eCollection 2024 Jul.

  PMID: 38911469 BACKGROUND

• DiNardo CD, Roboz GJ, Watts JM, Madanat YF, Prince GT, Baratam P, de Botton S, Stein A, Foran JM, Arellano ML, Sallman DA, Hossain M, Marchione DM, Bai X, Patel PA, Kapsalis SM, Garcia-Manero G, Fathi AT. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024 Aug 13;8(15):4209-4220. doi: 10.1182/bloodadvances.2023012302.

  PMID: 38640348 DERIVED

• Jiang X, Wada R, Poland B, Kleijn HJ, Fan B, Liu G, Liu H, Kapsalis S, Yang H, Le K. Population pharmacokinetic and exposure-response analyses of ivosidenib in patients with IDH1-mutant advanced hematologic malignancies. Clin Transl Sci. 2021 May;14(3):942-953. doi: 10.1111/cts.12959. Epub 2021 Jan 25.

  PMID: 33493392 DERIVED

• Choe S, Wang H, DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Watts JM, Pollyea DA, Fathi AT, Tallman MS, Kantarjian HM, Stone RM, Quek L, Konteatis Z, Dang L, Nicolay B, Nejad P, Liu G, Zhang V, Liu H, Goldwasser M, Liu W, Marks K, Bowden C, Biller SA, Attar EC, Wu B. Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Adv. 2020 May 12;4(9):1894-1905. doi: 10.1182/bloodadvances.2020001503.

  PMID: 32380538 DERIVED

• Fan B, Dai D, DiNardo CD, Stein E, de Botton S, Attar EC, Liu H, Liu G, Lemieux I, Agresta SV, Yang H. Clinical pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation. Cancer Chemother Pharmacol. 2020 May;85(5):959-968. doi: 10.1007/s00280-020-04064-6. Epub 2020 Apr 15.

  PMID: 32296873 DERIVED

• Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, Altman JK, Arellano ML, Donnellan W, Erba HP, Mannis GN, Pollyea DA, Stein AS, Uy GL, Watts JM, Fathi AT, Kantarjian HM, Tallman MS, Choe S, Dai D, Fan B, Wang H, Zhang V, Yen KE, Kapsalis SM, Hickman D, Liu H, Agresta SV, Wu B, Attar EC, Stone RM. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020 Feb 13;135(7):463-471. doi: 10.1182/blood.2019002140.

  PMID: 31841594 DERIVED

• DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, Kantarjian HM. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018 Jun 21;378(25):2386-2398. doi: 10.1056/NEJMoa1716984. Epub 2018 Jun 2.

  PMID: 29860938 DERIVED

• Birendra KC, DiNardo CD. Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. Clin Lymphoma Myeloma Leuk. 2016 Aug;16(8):460-5. doi: 10.1016/j.clml.2016.04.006. Epub 2016 May 5.

  PMID: 27245312 DERIVED

MeSH Terms

Conditions

Recurrence; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Hematologic Neoplasms

Interventions

ivosidenib

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases; Neoplasms by Site

Central Study Contacts

Institut de Recherches Internationales Servier Clinical Studies Department

CONTACT

+33 1 55 72 43 66; scientificinformation@servier.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2014
• First Posted: February 28, 2014
• Study Start: March 1, 2014
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: June 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• Access Criteria: Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.

Locations

US (26); FR (4)