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

A Phase I, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation

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.

Study Overview

• Status: Recruiting
• Conditions: Myelodysplastic Syndromes; Relapsed or Refractory Acute Myeloid Leukemia (AML); Untreated AML; Other IDH1-mutated Positive Hematologic Malignancies
• Intervention / Treatment: Drug: AG-120

• Study Type: Interventional
• Enrollment (Estimated): 291
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Institut de Recherches Internationales Servier Clinical Studies Department; Phone Number: +33 1 55 72 43 66; Email: scientificinformation@servier.com

Study Locations

• France
  • Marseille, France
    • Terminated
    • Hôpital La Timone
  • Pessac, France, 33600
    • Recruiting
    • Hôpital Haut-Lévêque
  • Pierre-Bénite, France, 69310
    • Recruiting
    • Central Lyon Sud
  • Villejuif, France, 94800
    • Recruiting
    • Institute Gustave Roussly (IGR)
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Active, not recruiting
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85259
      • Terminated
      • Mayo Clinic-AZ
  • California
    • Duarte, California, United States, 91010
      • Active, not recruiting
      • City of Hope
    • Los Angeles, California, United States, 90095
      • Terminated
      • University of California-Los Angeles
    • San Francisco, California, United States, 94143
      • Terminated
      • University of California-San Francisco
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Terminated
      • University of Colorado Denver
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Terminated
      • Mayo Clinic-Jacksonville
    • Miami, Florida, United States, 33136
      • Terminated
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Active, not recruiting
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Terminated
      • Northwestern University Medical Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Active, not recruiting
      • John Hopkins Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Terminated
      • Dana Farber Cancer Institute
    • Boston, Massachusetts, United States, 02214
      • Terminated
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Terminated
      • Karmanos Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Terminated
      • Washington University
  • New York
    • New York, New York, United States, 10021
      • Active, not recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10065
      • Terminated
      • Cornell Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Terminated
      • Duke Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44124
      • Withdrawn
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • Terminated
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Terminated
      • Oregon Health and Science University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Recruiting
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Terminated
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• 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.

Key Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AG-120; AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.	Drug: AG-120; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include (but are not limited to) maximum concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.	up to 26 weeks, on average
Pharmacodynamic relationship of AG-120 and 2-HG.	The potential relationship between plasma exposure of AG-120 and plasma, urine, or bone marrow 2-HG levels will be explored with descriptive and graphical methods.	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
Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Tmax) of AG-120 in subjects with R/R MDS.		up to 26 weeks, on average
Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (AUC) of AG-120 in subjects with R/R MDS.		up to 26 weeks, on average
Blood and bone marrow sampling at specified time points for determination of 2-HG levels to characterize the percent of 2-HG inhibition of AG-120 in plasma and bone marrow.		up to 26 weeks, on average

Collaborators and Investigators

• Sponsor: Institut de Recherches Internationales Servier

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Estimated): February 1, 2025
• Study Completion (Estimated): August 1, 2025

Study Registration Dates

• First Submitted: February 21, 2014
• First Submitted That Met QC Criteria: February 27, 2014
• First Posted (Estimated): February 28, 2014

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: AML; MDS; acute myeloid leukemia; hematologic malignancies; IDH; myelodysplastic syndrome; Untreated AML; IDH1; relapsed AML; refractory AML
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Leukemia; Neoplasms; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Ivosidenib
• Other Study ID Numbers: AG120-C-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.

Access can be requested for all interventional clinical studies:

• used for Marketing Authorization (MA) of medicines and new indications approved after 1 January 2014 in the European Economic Area (EEA) or the United States (US).
• where Servier is the Marketing Authorization Holder (MAH). The date of the first MA of the new medicine (or the new indication) in one of the EEA Member States will be considered for this scope.

In addition, access can be requested for all interventional clinical studies in patients:

• sponsored by Servier
• with a first patient enrolled as of 1 January 2004 onwards
• for New Chemical Entity or New Biological Entity (new pharmaceutical form excluded) for which development has been terminated before any Marketing authorization (MA) approval.

• IPD Sharing Time Frame: After Marketing Authorisation in EEA or US if the study is used for the approval.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Study Data/Documents

1. Individual Participant Data Set
2. Study Protocol
3. Statistical Analysis Plan
4. Informed Consent Form
5. Clinical Study Report
6. Study-level clinical trial data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No