study of orally administered ag-120 in subjects with advanced hematologic malignancies with an idh1 mutation

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

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.


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.

Keywords: acute myeloid leukemia aml myelodysplastic syndrome mds hematologic malignancies idh untreated aml idh1 relapsed aml refractory aml