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

Status: Recruiting
Phase:
Diagnosis: Leukemia/MDS
NCT ID: NCT02074839 (View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 14-035

 

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 three cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the MTD. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

 

Conducting Institutions:
Dana-Farber Cancer Institute, Brigham and Women's Hospital

Overall PI:
Richard Stone, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Contacts:
Dana-Farber Cancer Institute: Ilene Galinsky, 617-632-3902, igalinsky@partners.org

Eligibility Criteria

Key Inclusion Criteria: - Subject must be ≥18 years of age. - Subjects must have an advanced hematologic malignancy including: Relapsed and/or primary refractory AML as defined by WHO criteria; OR Untreated AML, ≥60 years of age and not candidates for standard therapy due to age, performance status, and/or adverse risk factors; OR Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the IPSS-R (Greenberg, et al. 2012), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition. - Subjects must have documented IDH1 gene-mutated disease based on local 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. Subjects with reproductive potential are defined as one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-120. Key Exclusion Criteria: - Subjects who have previously received AG-120. - 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 topical steroids 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 for up to 28 days after the start of AG-120 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL as well as prior to enrollment). - Subjects who received an investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥5 half-lives of the investigational agent has elapsed. - 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. - 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.
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