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

NCT02074839

Description:

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. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Related Conditions:
  • Hematopoietic and Lymphoid Malignancy
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AG120-C-001
  • NCT ID: NCT02074839

Conditions

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

Interventions

DrugSynonymsArms
AG-120AG-120

Purpose

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. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

Trial Arms

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

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/tolerability: incidence of adverse events
Time Frame:up to 26 weeks, on average
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies
Time Frame:up to 26 weeks, on average
Safety Issue:
Description:
Measure:Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies
Time Frame:up to 26 weeks, on average
Safety Issue:
Description: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.
Measure:Pharmacodynamic relationship of AG-120 and 2-HG
Time Frame:up to 26 weeks, on average
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Agios Pharmaceuticals, Inc.

Trial Keywords

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

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