Principal Investigator
Enrollment Status
Clinical Trial ID
Clinical Trial 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.
Phase
Phase 1
Funding Agency/Sponsor
Industrial
Disease
Leukemia
Enrollment Eligibility
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.