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
Overview
- Phase
- Phase 1
- Intervention
- AG-120
- Conditions
- Relapsed or Refractory Acute Myeloid Leukemia (AML)
- Sponsor
- Institut de Recherches Internationales Servier
- Enrollment
- 291
- Locations
- 30
- Primary Endpoint
- Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies.
- Status
- Recruiting
- Last Updated
- 10 months ago
Overview
Brief 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.
Investigators
Eligibility Criteria
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
- •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.
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 C1D
- •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.
Arms & Interventions
AG-120
AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.
Intervention: AG-120
Outcomes
Primary Outcomes
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: incidence of adverse events.
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
Secondary Outcomes
- Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies.(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.(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.(up to 26 weeks, on average)
- Pharmacodynamic relationship of AG-120 and 2-HG.(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).(up to 26 weeks, on average)
- Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies.(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.(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.(up to 26 weeks, on average)