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

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ClinicalTrials.gov Identifier: NCT02074839
Recruitment Status : Recruiting
First Posted : February 28, 2014
Last Update Posted : August 1, 2023
Sponsor:
Information provided by (Responsible Party):
Servier ( Institut de Recherches Internationales Servier )

Study Description
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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.

Condition or disease Intervention/treatment Phase
Relapsed or Refractory Acute Myeloid Leukemia (AML) Untreated AML Other IDH1-mutated Positive Hematologic Malignancies Myelodysplastic Syndromes Drug: AG-120 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 291 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : March 2014
Estimated Primary Completion Date : February 2025
Estimated Study Completion Date : August 2025

Resource links provided by the National Library of Medicine

Drug Information available for: Ivosidenib

Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. Safety/tolerability: incidence of adverse events. [ Time Frame: up to 26 weeks, on average ]
  2. Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies. [ Time Frame: up to 26 weeks, on average ]
  3. Assess clinical activity of AG-120 in subjects with relapsed or refractory AML who are enrolled in the Expansion Phase. [ Time Frame: up to 26 weeks, on average ]
  4. Safety/tolerability of treatment with AG-120 in subjects with relapsed or refractory myelodysplastic syndrome. [ Time Frame: up to 26 weeks, on average ]
  5. Assess clinical activity of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome. [ Time Frame: up to 26 weeks, on average ]

Secondary Outcome Measures :
  1. Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies. [ Time Frame: up to 26 weeks, on average ]
  2. Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies. [ Time Frame: up to 26 weeks, on average ]
    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.

  3. Pharmacodynamic relationship of AG-120 and 2-HG. [ Time Frame: up to 26 weeks, on average ]
    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.

  4. 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). [ Time Frame: up to 26 weeks, on average ]
  5. 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. [ Time Frame: up to 26 weeks, on average ]
  6. 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. [ Time Frame: up to 26 weeks, on average ]
  7. 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. [ Time Frame: up to 26 weeks, on average ]
  8. 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. [ Time Frame: up to 26 weeks, on average ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02074839


Contacts
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Contact: Institut de Recherches Internationales Servier Clinical Studies Department +33 1 55 72 43 66 scientificinformation@servier.com

Locations
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Sponsors and Collaborators
Institut de Recherches Internationales Servier
More Information
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Study Data/Documents: Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Study Protocol  This link exits the ClinicalTrials.gov site
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Informed Consent Form  This link exits the ClinicalTrials.gov site
Clinical Study Report  This link exits the ClinicalTrials.gov site
Study-level clinical trial data  This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Institut de Recherches Internationales Servier
ClinicalTrials.gov Identifier: NCT02074839    
Other Study ID Numbers: AG120-C-001
First Posted: February 28, 2014    Key Record Dates
Last Update Posted: August 1, 2023
Last Verified: July 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.
URL: https://clinicaltrials.servier.com/
Keywords provided by Servier ( Institut de Recherches Internationales Servier ):
acute myeloid leukemia
AML
myelodysplastic syndrome
MDS
hematologic malignancies
 IDH
Untreated AML
IDH1
relapsed AML
refractory AML
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Preleukemia
Hematologic Neoplasms
Myelodysplastic Syndromes
Leukemia
Neoplasms by Histologic Type
 Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms by Site
Ivosidenib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action