Clinical Trial 20838

Study Title

A Phase 1, 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, With a Substudy in Subjects With Relapsed or Refractory Myelodysplastic Syndrome and a Substudy in Subjects With Advanced Hematologic Malignancies With Organ Impairment

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.

Objective

Dose Escalation and Expansion Objectives: Primary: To assess the safety and tolerability of treatment with AG-120 administered continuously as a single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced hematologic malignancies. The initial dosing regimen was twice daily (approximately every 12 hours). Based on the emerging data, a once daily (approximately every 24 hours) dosing schedule has been implemented. Alternative dosing schedules, including administration of the same total daily dose using different dosing schedules in concurrent cohorts, may be explored as agreed upon by the Clinical Study Team. To determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of AG-120 in subjects with advanced hematologic malignancies. To assess the clinical activity of AG-120 in subjects with relapsed and/or refractory (R/R) acute myelogenous leukemia (AML) with an isocitrate dehydrogenase-1 (IDH1) mutation who are enrolled in Arm 1 of the expansion phase. Secondary: To describe the dose-limiting toxicities (DLTs) of AG-120 in subjects with advanced hematologic malignancies. To characterize the pharmacokinetics (PK) of AG-120 in subjects with advanced hematologic malignancies. To evaluate the PK/pharmacodynamic (PD) relationship of AG-120 and 2-hydroxygluturate (2-HG). To characterize the clinical activity associated with AG-120 in subjects with advanced hematologic malignancies. Exploratory: To characterize the PD effects of AG-120 in subjects with advanced hematologic malignancies by the assessment of: Changes in the patterns of cellular differentiation of IDH1-mutated and wild type cells. Changes in histone and deoxyribonucleic acid (DNA) methylation profiles in IDH1-mutated and wild type cells. To evaluate gene mutation status, global gene expression profiles, and other potential prognostic markers (cytogenetics) in IDH1-mutated cells and plasma, as well as subclonalpopulations of non-IDH1-mutated cells, to explore predictors of antitumor activity and/or resistance. To evaluate changes in the metabolic profiles in IDH1-mutated and wild type cells, urine and plasma. To monitor plasma cholesterol and 4â-OH-cholesterol levels as a potential cytochrome P450 (CYP) 3A4 induction marker for subjects enrolled in the dose escalation phase. MDS Substudy Objectives: Primary: To assess the safety and tolerability of treatment with AG-120 administered as 500 mg once daily (QD) dosed orally on Days 1 to 28 of a 28-day cycle in subjects with R/R myelodysplastic syndrome (MDS). To assess the clinical activity of AG-120 in subjects with R/R MDS. Secondary: To characterize the PK of AG-120 in subjects with R/R MDS. To evaluate the PK/PD relationship of plasma AG-120 and 2-HG. Organ Impairment Substudy Objectives: Primary: To assess the PK of AG-120 administered at 500 mg QD in subjects with IDH1-mutated hematologic malignancies with moderate hepatic impairment, severe hepatic impairment, or severe renal impairment compared with subjects with IDH1-mutated hematologic malignancies with adequate hepatic and renal function.