Pharmacokinetic/Pharmacodynamic Evaluation of Ivosidenib or Enasidenib Combined With Intensive Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed IDH1/2-Mutant Acute Myeloid Leukemia

Bin Fan, Yue Chen, Feng Yin, Lei Hua, Caroline Almon, Salah Nabhan, Michael Cooper, Hua Yang, Mohammad Hossain, Bin Fan, Yue Chen, Feng Yin, Lei Hua, Caroline Almon, Salah Nabhan, Michael Cooper, Hua Yang, Mohammad Hossain

Abstract

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, respectively. An open-label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib. Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2-HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration-time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2-HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2-HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2-HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.

Keywords: AML; PK/PD; enasidenib; isocitrate dehydrogenase; ivosidenib.

Conflict of interest statement

B.F., F.Y., L.H., C.A., S.N., M.C., H.Y., and M.H. were employees of and held stock/ownership interests in Agios at the time of this study. M.C. and M.H. are employees of Servier. Y.C. is an employee of and holds stock/ownership interests in Agios.

© 2022 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Study design and sampling schedule. aDuring induction and consolidation, sample collection occurred predose and at 0.5, 2, 4, 6, 8, and 24 h after dosing. bSampling for alternative enasidenib schedule (initiated C1D8) only. cPredose sampling only. AML, acute myeloid leukemia; ARA‐C, cytarabine; C, cycle; D, day; DNR, daunorubicin; ENA, enasidenib; IDR, idarubicin; IVO, ivosidenib; ME, mitoxantrone with etoposide; mIDH1/2, mutant IDH1/2; PD, pharmacodynamics; PK, pharmacokinetics; QD, once daily.
Figure 2
Figure 2
Plasma trough (predose) concentrations over time of ivosidenib or enasidenib in combination with chemotherapy. Cohorts for which enasidenib dosing was started on induction C1D1 or C1D8 are indicated by (D1) or (D8), respectively. Numbers above box plots represent numbers of patients. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. For timepoints with n

Figure 3

(A) Plasma 2‐HG reduction over…

Figure 3

(A) Plasma 2‐HG reduction over time before dosing and after multiple oral doses…

Figure 3
(A) Plasma 2‐HG reduction over time before dosing and after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy and (B) plasma 2‐HG reduction over time after multiple oral doses of enasidenib in combination with chemotherapy in patients with either IDH2‐R140 or IDH2‐R172 mutations. Cohorts for which enasidenib dosing was started on induction C1D1 or C1D8 are indicated by (D1) or (D8), respectively. Numbers above box plots represent numbers of patients. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. For time points with n aExcludes 1 patient at consolidation C1D1 with 2‐HG reduction lower than –100%. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.

Figure 4

Bone marrow 2‐HG reduction over…

Figure 4

Bone marrow 2‐HG reduction over time predose and after multiple oral doses of…

Figure 4
Bone marrow 2‐HG reduction over time predose and after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy. Cohorts for which enasidenib dosing was started on induction C1D1 or C1D8 are indicated by (D1) or (D8), respectively. Numbers above box plots represent numbers of patients. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. For timepoints with n < 5, data are presented as scatter plots with medians. Bone marrow 2‐HG concentrations reported as BLQ were set to the value of the LLOQ for PD analyses. aExcludes 1 patient at induction C1D22 (D8) with 2‐HG reduction lower than –100%. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.

Figure 5

2‐HG reduction vs C trough…

Figure 5

2‐HG reduction vs C trough for ivosidenib or enasidenib in combination with chemotherapy…

Figure 5
2‐HG reduction vs Ctrough for ivosidenib or enasidenib in combination with chemotherapy (induction C1D14). 2‐HG, D‐2‐hydroxyglutarate; C, cycle; Ctrough, observed concentration at the end of a dosing interval; D, day; ENA, enasidenib; IVO, ivosidenib; QD, once daily; Rtrough, observed response value at the end of a dosing interval.

Figure 6

Comparisons of 2‐HG concentrations in…

Figure 6

Comparisons of 2‐HG concentrations in bone marrow and plasma after oral doses of…

Figure 6
Comparisons of 2‐HG concentrations in bone marrow and plasma after oral doses of ivosidenib or enasidenib in combination with chemotherapy. Plasma BLQ values were set to the value of the LLOQ (ie, 30 ng/mL) owing to the endogenous nature of 2‐HG levels in humans. aExcludes 1 patient with unexpectedly high bone marrow 2‐HG level at induction C1D14 that exceeded the baseline level. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.

Figure 7

Plasma 2‐HG reduction at induction…

Figure 7

Plasma 2‐HG reduction at induction C1D14 by best overall response after multiple oral…

Figure 7
Plasma 2‐HG reduction at induction C1D14 by best overall response after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. 2‐HG, D‐2‐hydroxyglutarate; C, cycle; CR, complete remission; D, day; ENA, enasidenib; IR, incomplete remission (comprising CR with incomplete hematologic/platelet recovery, morphologic leukemia‐free state, and partial response); IVO, ivosidenib; NR, no response (comprising stable disease and progressive disease); QD, once daily.
All figures (7)
Figure 3
Figure 3
(A) Plasma 2‐HG reduction over time before dosing and after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy and (B) plasma 2‐HG reduction over time after multiple oral doses of enasidenib in combination with chemotherapy in patients with either IDH2‐R140 or IDH2‐R172 mutations. Cohorts for which enasidenib dosing was started on induction C1D1 or C1D8 are indicated by (D1) or (D8), respectively. Numbers above box plots represent numbers of patients. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. For time points with n aExcludes 1 patient at consolidation C1D1 with 2‐HG reduction lower than –100%. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.
Figure 4
Figure 4
Bone marrow 2‐HG reduction over time predose and after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy. Cohorts for which enasidenib dosing was started on induction C1D1 or C1D8 are indicated by (D1) or (D8), respectively. Numbers above box plots represent numbers of patients. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. For timepoints with n < 5, data are presented as scatter plots with medians. Bone marrow 2‐HG concentrations reported as BLQ were set to the value of the LLOQ for PD analyses. aExcludes 1 patient at induction C1D22 (D8) with 2‐HG reduction lower than –100%. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.
Figure 5
Figure 5
2‐HG reduction vs Ctrough for ivosidenib or enasidenib in combination with chemotherapy (induction C1D14). 2‐HG, D‐2‐hydroxyglutarate; C, cycle; Ctrough, observed concentration at the end of a dosing interval; D, day; ENA, enasidenib; IVO, ivosidenib; QD, once daily; Rtrough, observed response value at the end of a dosing interval.
Figure 6
Figure 6
Comparisons of 2‐HG concentrations in bone marrow and plasma after oral doses of ivosidenib or enasidenib in combination with chemotherapy. Plasma BLQ values were set to the value of the LLOQ (ie, 30 ng/mL) owing to the endogenous nature of 2‐HG levels in humans. aExcludes 1 patient with unexpectedly high bone marrow 2‐HG level at induction C1D14 that exceeded the baseline level. 2‐HG, D‐2‐hydroxyglutarate; BLQ, below the limit of quantification; C, cycle; D, day; ENA, enasidenib; IVO, ivosidenib; LLOQ, lower limit of quantification; QD, once daily.
Figure 7
Figure 7
Plasma 2‐HG reduction at induction C1D14 by best overall response after multiple oral doses of ivosidenib or enasidenib in combination with chemotherapy. Solid lines represent medians and boxes represent interquartile ranges. Error bars were calculated using Tukey's method. 2‐HG, D‐2‐hydroxyglutarate; C, cycle; CR, complete remission; D, day; ENA, enasidenib; IR, incomplete remission (comprising CR with incomplete hematologic/platelet recovery, morphologic leukemia‐free state, and partial response); IVO, ivosidenib; NR, no response (comprising stable disease and progressive disease); QD, once daily.

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