Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation
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|ClinicalTrials.gov Identifier: NCT02074839|
Recruitment Status : Recruiting
First Posted : February 28, 2014
Last Update Posted : September 14, 2022
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|Condition or disease||Intervention/treatment||Phase|
|Relapsed or Refractory Acute Myeloid Leukemia (AML) Untreated AML Other IDH1-mutated Positive Hematologic Malignancies Myelodysplastic Syndromes||Drug: AG-120||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||291 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
|Study Start Date :||March 2014|
|Estimated Primary Completion Date :||February 2025|
|Estimated Study Completion Date :||August 2025|
AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.
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.
- Safety/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. [ Time Frame: up to 26 weeks, on average ]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.
- Pharmacodynamic relationship of AG-120 and 2-HG. [ Time Frame: up to 26 weeks, on average ]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.
- 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 ]
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02074839
|Contact: Institut de Recherches Internationales Servier Clinical Studies Department||+33 1 55 72 43 firstname.lastname@example.org|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||Institut de Recherches Internationales Servier|
|Other Study ID Numbers:||
|First Posted:||February 28, 2014 Key Record Dates|
|Last Update Posted:||September 14, 2022|
|Last Verified:||September 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
Qualified scientific and medical researchers can request access to anonymized patient-level and study-level clinical trial data.
Access can be requested for all interventional clinical studies:
In addition, access can be requested for all interventional clinical studies in patients:
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
|Time Frame:||After Marketing Authorisation in EEA or US if the study is used for the approval.|
|Access Criteria:||Researchers should register on Servier Data Portal and fill in the research proposal form. This form in four parts should be fully documented. The Research Proposal Form will not be reviewed until all mandatory fields are completed.|
acute myeloid leukemia
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Bone Marrow Diseases
Neoplasms by Site
Molecular Mechanisms of Pharmacological Action