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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
291
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.
University of Alabama at Birmingham
Birmingham, Alabama, United States
ACTIVE_NOT_RECRUITINGMayo Clinic-AZ
Phoenix, Arizona, United States
TERMINATEDCity of Hope
Duarte, California, United States
ACTIVE_NOT_RECRUITINGUniversity of California-Los Angeles
Los Angeles, California, United States
TERMINATEDSafety/tolerability: incidence of adverse events.
Time frame: up to 26 weeks, on average
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
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
Safety/tolerability of treatment with AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.
Time frame: up to 26 weeks, on average
Assess clinical activity of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.
Time frame: up to 26 weeks, on average
Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies.
Time frame: up to 26 weeks, on average
Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies.
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.
Time frame: up to 26 weeks, on average
Pharmacodynamic relationship of AG-120 and 2-HG.
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.
Time frame: up to 26 weeks, on average
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
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
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
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
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
Institut de Recherches Internationales Servier Clinical Studies Department
CONTACT
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University of California-San Francisco
San Francisco, California, United States
TERMINATEDUniversity of Colorado Denver
Aurora, Colorado, United States
TERMINATEDMayo Clinic-Jacksonville
Jacksonville, Florida, United States
TERMINATEDUniversity of Miami
Miami, Florida, United States
TERMINATEDMoffit Cancer Center
Tampa, Florida, United States
ACTIVE_NOT_RECRUITINGEmory University
Atlanta, Georgia, United States
ACTIVE_NOT_RECRUITING...and 20 more locations