TIBSOVO Film-coated tablet Ref.[10343] Active ingredients: Ivosidenib

Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies to levels similar to those observed at baseline in healthy subjects. In bone marrow, 2-HG concentrations were reduced by >90%.

Cardiac Electrophysiology

A concentration-dependent QTc interval prolongation of approximately 17.2 msec (90% CI: 14.7, 19.7) was observed at the steady-state C_max following a 500 mg daily dose based on an analysis of 171 patients with advanced hematologic malignances and an IDH1 mutation, including 26 patients with newly diagnosed AML and 136 patients with relapsed or refractory AML, who received TIBSOVO 500 mg daily [see Warnings and Precautions (5.1)]. Co-administration with moderate or strong CYP3A inhibitors is expected to further increase QTc interval prolongation from baseline.

The following ivosidenib pharmacokinetic parameters were observed following administration of ivosidenib 500 mg as a single dose or daily dose (for steady-state), unless otherwise specified. The steady-state pharmacokinetics of ivosidenib 500 mg were comparable between patients with newly diagnosed AML and patients with relapsed or refractory AML.

The mean peak plasma concentration (C_max) is 4,503 ng/mL [% coefficient of variation (%CV: 38)] after a single dose, and 6,551 ng/mL (%CV: 44) at steady-state. The steady-state area under the concentration time curve (AUC) is 117,348 ng·hr/mL (%CV: 50).

The AUC and C_max of ivosidenib increase in a less than dose-proportional manner from 200 mg to 1,200 mg daily (0.4 to 2.4 times the approved recommended dosage). Accumulation ratios were approximately 1.9 for AUC and 1.5 for C_max over one month. Steady-state plasma levels are reached within 14 days.

Absorption

The median time to C_max is approximately 3 hours.

Effect of Food

Following administration of a single dose in healthy subjects, a high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat calories, 250 carbohydrate calories and 150 protein calories) increased ivosidenib C_max by 98% (90% CI: 79%, 119%) and AUC_inf by approximately 25%.

Distribution

The mean apparent volume of distribution of ivosidenib at steady-state is 234 L (CV: 47). Protein binding of ivosidenib ranges from 92 to 96 in vitro.

Elimination

Ivosidenib has a terminal half-life of 93 hours (%CV: 67) and an apparent clearance (CL/F) of 4.3 L/hour (%CV: 50).

Metabolism

Ivosidenib is the predominant component (>92%) of total radioactivity in plasma. Ivosidenib is primarily metabolized by CYP3A4 with minor contributions by N-dealkylation and hydrolytic pathways.

Excretion

After a single oral administration of radiolabeled ivosidenib to healthy subjects, 77% of ivosidenib was eliminated in the feces (67% as unchanged) and 17% in the urine (10% as unchanged).

Specific Populations

No clinically meaningful effects on the pharmacokinetics of ivosidenib were observed based on age (18 years to 89 years), sex, race (White, Asian, Black or African American), body weight (38 to 150 kg), ECOG performance status, or mild or moderate renal impairment (eGFR ≥30 mL/min/1.73m², MDRD). The pharmacokinetics of ivosidenib in patients with severe renal impairment (eGFR <30 mL/min/1.73m², MDRD) or renal impairment requiring dialysis is unknown.

Patients with Hepatic Impairment

Following a single dose of TIBSOVO 500 mg, the geometric mean ratio (90% confidence interval) of ivosidenib systemic exposure (AUC_0-INF) in subjects with mild hepatic impairment (Child-Pugh A) was 0.85 (0.62, 1.15) and moderate hepatic impairment (Child-Pugh B) was 0.71 (0.48, 1.05) as compared to that in subjects with normal hepatic function. The pharmacokinetics of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) is unknown.

Drug Interaction Studies

Clinical Studies and Model-Based Approaches

Effect of Strong or Moderate CYP3A4 Inhibitors on Ivosidenib:

Itraconazole was used as a strong CYP3A4 index inhibitor to evaluate the effect of CYP3A4 inhibition on the pharmacokinetics of ivosidenib single-dose in a drug-drug interaction study in healthy subjects. Co-administration of 250 mg ivosidenib with itraconazole (200 mg itraconazole once daily for 18 days) increased ivosidenib single-dose AUC to 269% of control (90% CI: 245%, 295%) with no change in C_max. In regards to multiple-dosing, note that because ivosidenib induces the metabolism of CYP3A4 substrates following ivosidenib multiple dosing, itraconazole (a CYP3A4 substrate) is not recommended to be used concomitantly with TIBSOVO in patients (see Effect of Ivosidenib on CYP3A4 Substrates).

Based on physiologically-based pharmacokinetic modeling, co-administration of 500 mg ivosidenib with the moderate CYP3A4 inhibitor fluconazole (dosed to steady-state) is predicted to increase ivosidenib single-dose AUC to 173% of control with no change in C_max. In regards to multiple-dosing, co-administration with ivosidenib and fluconazole is predicted to increase ivosidenib steady-state C_max to 152% of control and AUC to 190% of control [see Drug Interactions (7.1)].

Effect of Strong CYP3A4 Inducers on Ivosidenib:

Co-administration of ivosidenib with a strong CYP3A4 inducer (600 mg rifampin once daily for 15 days) is predicted to decrease ivosidenib steady-state AUC by 33% [see Drug Interactions (7.1)].

Effect of Ivosidenib on CYP3A4 Substrates:

Ivosidenib induces CYP3A4, including its own metabolism. Co-administration of ivosidenib with CYP3A4 substrates such as itraconazole is expected to decrease itraconazole steady-state AUC to a clinically relevant extent [see Drug Interactions (7.2)].

Effect of Gastric Acid Reducing Agents on Ivosidenib:

Gastric acid reducing agents (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) do not affect ivosidenib concentrations.

In vitro Studies

Metabolic Pathways:

Ivosidenib may induce CYP2B6, CYP2C8, and CYP2C9 and therefore may affect the pharmacokinetics of sensitive substrates of these enzymes [see Drug Interactions (7.2)].

Drug Transporter Systems:

Ivosidenib is a substrate for P-glycoprotein (P-gp). Ivosidenib is not a substrate for BCRP or hepatic transporters OATP1B1 and OATP1B3.

Ivosidenib does not inhibit BCRP, OATP1B1, OATP1B3, OAT1, and OCT2 at clinically relevant concentrations. Ivosidenib is an inhibitor of OAT3 and P-gp.

Carcinogenicity studies have not been conducted with ivosidenib. Ivosidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Ivosidenib was not clastogenic in an in vitro human lymphocyte micronucleus assay, or in an in vivo rat bone marrow micronucleus assay. Fertility studies in animals have not been conducted with ivosidenib. In repeat-dose toxicity studies up to 90 days in duration with twice daily oral administration of ivosidenib in rats, uterine atrophy was reported in females at non-tolerated dose levels.

14.1 Newly-Diagnosed AML

The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) that included 28 adult patients with newly-diagnosed AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime IDH1 Assay. The cohort included patients who were age 75 years or older or who had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of ≥2, severe cardiac or pulmonary disease, hepatic impairment with bilirubin >1.5 times the upper limit of normal, or creatinine clearance <45 mL/min. TIBSOVO was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Two (7%) of the 28 patients went on to stem cell transplantation following TIBSOVO treatment.

The baseline demographic and disease characteristics are shown in Table 6.

Table 6. Baseline Demographic and Disease Characteristics in Patients with Newly-Diagnosed AML (Study AG120-C-001):

ECOG PS: Eastern Cooperative Oncology Group Performance Status. ELN: European Leukemia Net
¹ Using confirmatory Abbott RealTime IDH1 assay testing results.
² Patients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO.
³ AML with myelodysplasia-related changes.

Efficacy was established on the basis of the rate of complete remission (CR) or complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 7. The median follow-up was 8.1 months (range, 0.6 to 40.9 months) and median treatment duration was 4.3 months (range, 0.3 to 40.9 months).

Table 7. Efficacy Results in Patients with Newly-Diagnosed AML (Study AG120-C-001):

CI: confidence interval, NE: not estimable
¹ CR (complete remission) was defined as <5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC] >1,000/microliter).
² DOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier. + indicates censored observation.
³ The median durations of CR and CR+CRh were not estimable, with 5 patients (41.7%) who achieved CR or CRh remaining on TIBSOVO treatment (treatment duration range: 20.3 to 40.9 months).
⁴ CRh (complete remission with partial hematological recovery) was defined as <5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).

For patients who achieved a CR or CRh, the median time to CR or CRh was 2.8 months (range, 1.9 to 12.9 months). Of the 12 patients who achieved a best response of CR or CRh, 11 (92%) achieved a first response of CR or CRh within 6 months of initiating TIBSOVO.

Among the 17 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 7 (41.2%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 11 patients who were independent of both RBC and platelet transfusions at baseline, 6 (54.5%) remained transfusion independent during any 56-day post-baseline period.

14.2 Relapsed or Refractory AML

The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter clinical trial (Study AG120-C-001, NCT02074839) of 174 adult patients with relapsed or refractory AML with an IDH1 mutation. IDH1 mutations were identified by a local or central diagnostic test and confirmed retrospectively using the Abbott RealTime IDH1 Assay. TIBSOVO was given orally at a starting dose of 500 mg daily until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. Twenty-one (12%) of the 174 patients went on to stem cell transplantation following TIBSOVO treatment.

The baseline demographic and disease characteristics are shown in Table 8.

Table 8. Baseline Demographic and Disease Characteristics in Patients with Relapsed or Refractory AML (Study AG120-C-001):

ECOG PS: Eastern Cooperative Oncology Group Performance Status.
¹ Using confirmatory Abbott RealTime IDH1 assay testing results.
² Patients were defined as transfusion dependent at baseline if they received any transfusion occurring within 56 days prior to the first dose of TIBSOVO.

Efficacy was established on the basis of the rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh), the duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in Table 9. The median follow-up was 8.3 months (range, 0.2 to 39.5 months) and median treatment duration was 4.1 months (range, 0.1 to 39.5 months).

Table 9. Efficacy Results in Patients with Relapsed or Refractory AML (Study AG120-C-001):

CI: confidence interval
¹ CR (complete remission) was defined as <5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets >100,000/microliter and absolute neutrophil counts [ANC] >1,000/microliter).
² DOCR (duration of CR), DOCRh (duration of CRh), and DOCR+CRh (duration of CR+CRh) was defined as time since first response of CR, CRh or CR/CRh, respectively, to relapse or death, whichever is earlier.
³ CRh (complete remission with partial hematological recovery) was defined as <5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter).
⁴ CR+CRh rate appeared to be consistent across all baseline demographic and baseline disease characteristics with the exception of number of prior regimens.

For patients who achieved a CR or CRh, the median time to CR or CRh was 2 months (range, 0.9 to 5.6 months). Of the 57 patients who achieved a best response of CR or CRh, all achieved a first response of CR or CRh within 6 months of initiating TIBSOVO.

Among the 110 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 41 (37.3%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 64 patients who were independent of both RBC and platelet transfusions at baseline, 38 (59.4%) remained transfusion independent during any 56-day post-baseline period.