Longitudinal Pharmacokinetic/Pharmacodynamic Profile of AG-120, a Potent Inhibitor of the IDH1 Mutant Protein, in a Phase 1 Study of IDH1-Mutant Advanced Hematologic Malignancies

INTRODUCTION: Somatic IDH1/2 mutations occur in multiple solid and hematologic tumors, including acute myeloid leukemia. Mutant IDH1/2 proteins have novel enzymatic activity, catalyzing the reduction of α-ketoglutarate to produce the oncometabolite, D-2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes including impaired cellular differentiation. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of the mutated IDH1 protein, and has been shown to lower 2-HG levels and restore cellular differentiation in IDH1-mutant primary human blast cells cultured ex vivo. AG-120 is currently being assessed in a first-in-human, phase 1 study enrolling patients with IDH1-mutant, advanced hematologic malignancies (NCT02074839). Our objective was to further assess the longitudinal pharmacokinetic/pharmacodynamic (PK/PD) data from the ongoing phase 1 study, including dose proportionality assessment of AG-120 exposure after single and multiple doses over time, and the influence of patient-intrinsic factors.

METHODS: The AG-120 phase 1, open-label, dose-escalation and expansion study includes evaluation of safety, tolerability, maximum tolerated dose, PK/PD (including 2-HG levels) and clinical activity. Single-agent AG-120 is administered orally once (QD) or twice (BID) daily in continuous 28-day cycles. Patients included in this analysis received doses of 100 mg BID, 300 mg QD, 500 mg QD, 800 mg QD and 1200 mg QD (N=39). Blood, bone marrow and urine samples were collected at multiple time points for determination of PK/PD using qualified LC-MS/MS-based methods. Analyses were performed using WinNonLin^®.

RESULTS: AG-120 exposure exceeding the predicted efficacious exposure level was demonstrated at all dose levels following oral administration. Following both single (Day -3) and multiple (Cycle 1 Day 15 [C1D15] and Cycle 2 Day 1) dose administration, mean plasma exposures of AG-120 increased less than proportionally to dose, although plasma exposures were quite variable within dose levels. Preliminary PK data revealed a mean half-life of 119 ± 104 hr. Following multiple doses, most patients achieved steady state in Cycle 1, with ~2 to 3-fold accumulation in plasma observed. Furthermore, pre-dose AG-120 trough levels were maintained above the predicted efficacious exposure level throughout treatment (up to 11 cycles). Following a single dose of AG-120, plasma 2-HG levels gradually reduced over 3 days. After multiple doses, plasma 2-HG levels were reduced to levels seen in healthy volunteers (up to 99.7% inhibition) at all dose levels tested. Steady state 2-HG inhibition was reached at approximately C1D15 in most patients, and was maintained over the course of treatment (up to 11 cycles). Mean bone marrow 2-HG levels were also substantially reduced following multiple doses of AG-120 at all dose levels tested (up to 99.9% reduction compared with baseline). Plasma 2-HG levels showed a positive correlation with levels in bone marrow (r²=0.882, p<0.001) and urine (r²=0.528, p<0.001), with a stronger correlation being observed with the former tissue. There was no clear effect of patient-intrinsic factors such as body weight or body surface area on C_maxor AUC within the ranges tested, although the current sample size is small. Population PK and PK/PD assessments will be conducted to confirm these findings. These analyses are based on data as of 1 May 2015; updated analyses will be presented.

CONCLUSION: AG-120 exposure increased less than proportionally to dose following oral administration, with long half-life and maintenance of pre-dose levels above the predicted efficacious exposure, supporting QD dosing. In patients with IDH1 mutations, AG-120 inhibited plasma 2-HG to within levels found in healthy volunteers, and also inhibited 2-HG in bone marrow.