1.1 Newly Diagnosed Acute Myeloid Leukemia

TIBSOVO is indicated in combination with azacitidine or as monotherapy for the treatment of newly diagnosed acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy [see Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14.1)].

1.2 Relapsed or Refractory Acute Myeloid Leukemia

TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14.2)].

1.3 Relapsed or Refractory Myelodysplastic Syndromes

TIBSOVO is indicated for the treatment of adult patients with relapsed or refractory myelodysplastic syndromes (MDS) with a susceptible isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology (12.1) and Clinical Studies (14.3)].

1.4 Locally Advanced or Metastatic Cholangiocarcinoma

TIBSOVO is indicated for the treatment of adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test [see Dosage and Administration (2.1), Clinical Pharmacology (12.1), and Clinical Studies (14.4)].

2.1 Patient Selection

Select patients for treatment with TIBSOVO based on the presence of IDH1 mutations [see Clinical Studies (14.1, 14.2, 14.3, 14.4)].

Information on FDA-approved tests for the detection of IDH1 mutations in AML, MDS, and cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage

The recommended dosage of TIBSOVO is 500 mg taken orally once daily until disease progression or unacceptable toxicity [see Clinical Studies (14.1, 14.2, 14.3, 14.4)].

For patients with AML or MDS without disease progression or unacceptable toxicity, continue TIBSOVO for a minimum of 6 months to allow time for clinical response.

• Administer TIBSOVO with or without food.
• Do not administer TIBSOVO with a high-fat meal [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
• Do not split, crush, or chew TIBSOVO tablets.
• Administer TIBSOVO tablets orally about the same time each day.
• If a dose of TIBSOVO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.
• If a dose of TIBSOVO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day. Do not administer 2 doses within 12 hours.

2.3 Monitoring and Dosage Modifications for Toxicities

Obtain an electrocardiogram (ECG) prior to treatment initiation. Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy [see Warnings and Precautions (5.2)]. Manage any abnormalities promptly.

Interrupt dosing or reduce dose for toxicities. See Table 1 for dosage modification guidelines.

2.4 Dosage Modification for Use with Strong CYP3A4 Inhibitors

If a strong CYP3A4 inhibitor must be coadministered, reduce the TIBSOVO dose to 250 mg once daily. If the strong inhibitor is discontinued, increase the TIBSOVO dose (after at least 5 half-lives of the strong CYP3A4 inhibitor) to the recommended dose of 500 mg once daily.

5.1 Differentiation Syndrome in AML and MDS

Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal.

Symptoms of differentiation syndrome in patients treated with TIBSOVO included noninfectious leukocytosis, peripheral edema, pyrexia, dyspnea, pleural effusion, hypotension, hypoxia, pulmonary edema, pneumonitis, pericardial effusion, rash, fluid overload, tumor lysis syndrome and creatinine increased.

In the combination study AG120-C-009, 15% (11/71) patients with newly diagnosed AML treated with TIBSOVO plus azacitidine experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 11 patients with newly diagnosed AML who experienced differentiation syndrome with TIBSOVO plus azacitidine 8 (73%) recovered. Differentiation syndrome occurred as early as 3 days after start of therapy and during the first month on treatment.

In the monotherapy clinical trial AG120-C-001, 25% (7/28) of patients with newly diagnosed AML and 19% (34/179) of patients with relapsed or refractory AML treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 7 patients with newly diagnosed AML who experienced differentiation syndrome, 6 (86%) patients recovered. Of the 34 patients with relapsed or refractory AML who experienced differentiation syndrome, 27 (79%) patients recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

In the monotherapy clinical trial AG120-C-001, 11% (2/19) of patients with relapsed or refractory MDS treated with TIBSOVO experienced differentiation syndrome [see Adverse Reactions (6.1)]. Of the 2 patients who experienced differentiation syndrome, both recovered after treatment or after dose interruption of TIBSOVO. Differentiation syndrome occurred as early as 1 day and up to 3 months after TIBSOVO initiation and has been observed with or without concomitant leukocytosis.

If differentiation syndrome is suspected, initiate dexamethasone 10 mg IV every 12 hours (or an equivalent dose of an alternative oral or IV corticosteroid) and hemodynamic monitoring until improvement [see Dosage and Administration (2.3)]. If concomitant noninfectious leukocytosis is observed, initiate treatment with hydroxyurea or leukapheresis, as clinically indicated. Taper corticosteroids and hydroxyurea after resolution of symptoms and administer corticosteroids for a minimum of 3 days. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid and/or hydroxyurea treatment. If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroids, interrupt TIBSOVO until signs and symptoms are no longer severe [see Dosage and Administration (2.3)].

5.2 QTc Interval Prolongation

Patients treated with TIBSOVO can develop QT (QTc) prolongation and ventricular arrhythmias [see Clinical Pharmacology (12.2)].

Of the 71 patients with newly diagnosed AML treated with TIBSOVO in combination with azacitidine in the clinical trial (Study AG120-C-009), 10 (14%) were found to have a heart-rate corrected QT interval (using Fridericia's method) (QTcF) greater than 500 msec and 15 out of 69 (22%) had an increase from baseline QTcF greater than 60 msec [see Adverse Reactions (6.1)]. The clinical trial excluded patients with a QTcF ≥ 470 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g. NYHA Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome).

Of the 265 patients with hematological malignancies, including patients with AML and MDS, treated with TIBSOVO monotherapy in the clinical trial (AG120-C-001), 9% were found to have a QTc interval greater than 500 msec and 14% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1)]. One patient developed ventricular fibrillation attributed to TIBSOVO. The clinical trial excluded patients with baseline QTc of ≥ 450 msec (unless the QTc ≥ 450 msec was due to a pre-existing bundle branch block) or with a history of long QT syndrome or uncontrolled or significant cardiovascular disease.

Of the 123 patients with cholangiocarcinoma treated with TIBSOVO in the clinical trial (Study AG120-C-005), 2% were found to have a QTc interval greater than 500 msec and 5% of patients had an increase from baseline QTc greater than 60 msec [see Adverse Reactions (6.1)]. The clinical trial excluded patients with a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) ≥ 450 msec or other factors that increased the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).

Concomitant use of TIBSOVO with drugs known to prolong the QTc interval (e.g., anti-arrhythmic medicines, fluoroquinolones, triazole anti-fungals, 5-HT3 receptor antagonists) and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7.1), Clinical Pharmacology (12.2)]. Conduct monitoring of electrocardiograms (ECGs) and electrolytes [see Dosage and Administration (2.3)].

In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent monitoring may be necessary.

Interrupt TIBSOVO if QTc increases to greater than 480 msec and less than 500 msec. Interrupt and reduce TIBSOVO if QTc increases to greater than 500 msec. Permanently discontinue TIBSOVO in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia [See Dosage and Administration (2.3)].

5.3 Guillain-Barré Syndrome

Guillain-Barré syndrome can develop in patients treated with TIBSOVO. Guillain-Barré syndrome occurred in 0.8% (2/265) of patients treated with TIBSOVO in study AG120-C-001 [see Adverse Reactions (6.1)].

Monitor patients taking TIBSOVO for onset of new signs or symptoms of motor and/or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, paresthesias, or difficulty breathing. Permanently discontinue TIBSOVO in patients who are diagnosed with Guillain-Barré syndrome [see Dosage and Administration (2.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

7.1 Effect of Other Drugs on Ivosidenib

7.2 Effect of Ivosidenib on Other Drugs

Ivosidenib induces CYP3A4 and may induce CYP2C9. Co-administration will decrease concentrations of drugs that are sensitive CYP3A4 substrates and may decrease concentrations of drugs that are sensitive CYP2C9 substrates [see Clinical Pharmacology (12.3)]. Use alternative therapies that are not sensitive substrates of CYP3A4 and CYP2C9 during TIBSOVO treatment. If co-administration of TIBSOVO with sensitive CYP3A4 substrates or CYP2C9 substrates is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

Do not administer TIBSOVO with anti-fungal agents that are substrates of CYP3A4 due to expected loss of antifungal efficacy.

Co-administration of TIBSOVO may decrease the concentrations of hormonal contraceptives, consider alternative methods of contraception in patients receiving TIBSOVO.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of TIBSOVO in pediatric patients have not been established.

8.5 Geriatric Use

Of the 304 patients who received TIBSOVO in the clinical studies for AML and MDS, 75% were 65 years of age or older and 35% were 75 years or older.

Of the 124 patients with cholangiocarcinoma treated with TIBSOVO in Study AG120-C-005, 37% were 65 years of age or older and 11% were 75 years or older.

No overall differences in effectiveness or safety were observed between patients who were 65 years and older compared to younger patients.

8.6 Renal Impairment

No modification of the starting dose is recommended for patients with mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73m2, MDRD). The pharmacokinetics and safety of ivosidenib in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2, MDRD) or renal impairment requiring dialysis are unknown [see Clinical Pharmacology (12.3)]. For patients with pre-existing severe renal impairment or who are requiring dialysis, consider the risks and potential benefits before initiating treatment with TIBSOVO.

8.7 Hepatic Impairment

No modification of the starting dose is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment [see Clinical Pharmacology (12.3)]. The pharmacokinetics and safety of ivosidenib in patients with severe hepatic impairment (Child-Pugh C) are unknown. For patients with pre-existing severe hepatic impairment, consider the risks and potential benefits before initiating treatment with TIBSOVO.

12.1 Mechanism of Action

Ivosidenib is a small molecule inhibitor that targets the mutant isocitrate dehydrogenase 1 (IDH1) enzyme. In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of ivosidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of ivosidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions.

Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much lower concentrations than wild-type IDH1 in vitro. Inhibition of the mutant IDH1 enzyme by ivosidenib led to decreased 2-HG levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH1-mutated AML. In blood samples from patients with AML with mutated IDH1, ivosidenib decreased 2-HG levels ex-vivo, reduced blast counts, and increased percentages of mature myeloid cells.

In a patient-derived xenograft intra-hepatic cholangiocarcinoma mouse model with IDH1 R132C, ivosidenib reduced 2-HG levels.

12.2 Pharmacodynamics

Multiple doses of ivosidenib 500 mg daily were observed to decrease plasma 2-HG concentrations in patients with hematological malignancies and cholangiocarcinoma to levels similar to those observed at baseline in healthy subjects. In bone marrow of patients with hematological malignancies and in tumor biopsy of patients with cholangiocarcinoma, the mean [% coefficient of variation (%CV)] reduction in 2-HG concentrations were 93.1% (11.1%) and 82.2% (32.4%), respectively.

12.3 Pharmacokinetics

The AUC and Cmax 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). The following ivosidenib pharmacokinetic parameters (Table 12) 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, relapsed or refractory AML, and relapsed or refractory MDS, and were lower in patients with cholangiocarcinoma.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Newly Diagnosed AML in Combination with Azacitidine

The efficacy of TIBSOVO was evaluated in a randomized (1:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-009, NCT03173248) of 146 adult patients with newly-diagnosed AML with an IDH1 mutation who were 75 years or older, or 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, creatinine clearance < 45 mL/min, or other comorbidity. IDH1 mutations were confirmed centrally using the Abbott RealTime™ IDH1 Assay. Local diagnostic tests were permitted for screening and randomization provided a bone marrow or peripheral blood sample was sent for central confirmation. Gene mutation analysis to document IDH1 mutated disease from a bone marrow or peripheral blood sample was conducted for all patients. Patients were randomized to receive either TIBSOVO 500 mg or matched placebo orally once daily on Days 1-28 in combination with azacitidine 75 mg/m2/day either subcutaneously or intravenously on Days 1-7 or Days 1-5 and 8-9 of each 28-day cycle beginning on Cycle 1 Day 1. Patients were treated for a minimum of 6 cycles unless they experienced disease progression, unacceptable toxicity or undergoing hematopoietic stem cell transplantation. Baseline demographic and disease characteristics are shown in Table 13.

Table 13: Baseline Demographic and Disease Characteristics in Patients with Newly Diagnosed AML (Study AG120-C-009)

Demographic and Disease Characteristics	TIBSOVO + azacitidine (500 mg daily) N=72	Placebo + azacitidine N=74
ECOG PS: Eastern Cooperative Oncology Group Performance Status; MPN = Myeloproliferative Neoplasm; MDS = Myelodysplastic syndrome
* Using confirmatory Abbott RealTime IDH1 assay testing results. † Cytogenetic risk status: National Comprehensive Cancer Network (NCCN) guidelines. ‡ Patients were defined as transfusion dependent at baseline if they received any red blood cell or platelet transfusion within 56 days prior to the first dose of TIBSOVO.
Demographics
Age (Years) Median (Min, Max)	76 (58, 84)	76 (45, 94)
Age Categories, n (%)
<65 years	4 (6)	4 (5)
≥65 years to <75 years	29 (40)	27 (36)
≥75 years	39 (54)	43 (58)
Sex, n (%)
Male	42 (58)	38 (51)
Female	30 (42)	36 (49)
Race, n (%)
Asian	15 (21)	19 (26)
White	12 (17)	12 (16)
Black or African American	0	2 (3)
Other	1 (1)	1 (1)
Not provided	44 (61)	40 (54)
Disease Characteristics
ECOG PS, n (%)
0	14 (19)	10 (14)
1	32 (44)	40 (54)
2	26 (36)	24 (32)
IDH1 Mutation, n (%)*
R132C	45 (63)	51 (69)
R132H	14 (19)	12 (16)
R132G	6 (8)	4 (5)
R132L	3 (4)	0
R132S	2 (3)	6 (8)
Wild type	1 (1)	0
Missing	1 (1)	1 (1)
Cytogenetic risk status† n (%)
Favorable	3 (4)	7 (9)
Intermediate	48 (67)	44 (59)
Poor	16 (22)	20 (27)
Other	3 (4)	1 (1)
Missing	2 (3)	2 (3)
Transfusion Dependent at Baseline‡, n (%)	39 (54)	40 (54)
Type of AML, n (%)
De novo AML	54 (75)	53 (72)
Secondary AML	18 (25)	21 (28)
Therapy-related AML	2 (3)	1 (1)
MDS related	10 (14)	12 (16)
MPN related	4 (6)	8 (11)

Efficacy was established on the basis of event-free survival (EFS), overall survival (OS), and rate and duration of complete remission (CR). EFS was defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurred first. Treatment failure was defined as failure to achieve CR by 24 weeks. The efficacy results are shown in Table 14 and Figure 1.

Table 14: Efficacy Results in Patients with Newly Diagnosed AML (Study AG120-C-009)

Endpoint	TIBSOVO (500 mg daily) + azacitidine N=72	Placebo + azacitidine N=74
Abbreviations: EFS = Event free survival; CI: confidence interval; OS = Overall survival; CR = Complete remission; CRh = Complete remission with partial hematologic recovery; NE = Not estimable.
The 2-sided p-value boundaries for EFS, OS, CR, and CR+CRh are 0.0095, 0.0034, 0.0174, and 0.0174, respectively.
* Hazard ratio is estimated using a Cox's proportional hazards model stratified by the randomization stratification factors (AML status and geographic region) with Placebo+ azacitidine as the denominator. † Two-sided p-value is calculated from the log-rank test stratified by the randomization stratification factors (AML status and geographic region). ‡ CI of percentage is calculated with the Clopper and Pearson (exact Binomial) method. § Mantel-Haenszel estimate of risk difference in percentage between TIBSOVO + azacitidine and Placebo+ azacitidine is calculated. ¶ Two-sided p-value is calculated from the Cochran-Mantel-Haenszel test stratified by the randomization stratification factors (AML status and geographic region).
EFS, events (%)	47 (65)	62 (84)
Treatment Failure	43 (60)	59 (80)
Relapse	3 (4)	2 (3)
Death	1 (1)	1 (1)
Hazard ratio* (95% CI)	0.35 (0.17, 0.72)
p-value†	0.0038
OS events (%)	28 (39)	46 (62)
Median OS (95% CI) months	24.0 (11.3, 34.1)	7.9 (4.1, 11.3)
Hazard ratio* (95% CI)	0.44 (0.27, 0.73)
p-value†	0.0010
CR, n (%)	34 (47)	11 (15)
95% CI‡	(35, 59)	(8, 25)
Risk difference§ (95% CI), (%)	31 (17, 46)
p-value¶	<0.0001
Median duration of CR (95% CI), months	NE (13.0, NE)	11.2 (3.2, NE)
CR +CRh, n (%)	37 (51)	13 (18)
95% CI‡	(39, 63)	(10, 28)
Risk difference§ (95% CI), (%)	33 (18, 47)
p-value¶	<0.0001
Median duration of CR + CRh (95% CI), months	NE (13.0, NE)	9.2 (5.8, NE)

Figure 1: Kaplan-Meier Curve for Overall Survival in AG120-C-009

The median time to first CR for TIBSOVO with azacitidine was 4 months (range, 1.7 to 11.9 months).

The median time to first CR + CRh for TIBSOVO with azacitidine was 4 months (range, 1.7 to 11.9 months).

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 17.

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 18. 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).

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.

14.3 Relapsed or Refractory MDS

The efficacy of TIBSOVO was evaluated in an open-label, single-arm, multicenter study (study AG120-C-001, NCT02074839) of 18 adult patients with relapsed or refractory MDS with an IDH1 mutation. IDH1 mutations were detected in peripheral blood or bone marrow 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 continuous for 28-day cycles until disease progression, development of unacceptable toxicity, or undergoing hematopoietic stem cell transplantation. One (6%) of the 18 patients went on to stem cell transplantation following TIBSOVO treatment.

The baseline demographic and disease characteristics are shown in Table 19.

Efficacy was established on the basis of the rate of complete remission (CR) or partial remission (PR) as per the 2006 International Working Group response criteria for MDS, the duration of CR+PR, and the rate of conversion from transfusion dependence to transfusion independence. All observed responses were CRs. The efficacy results are shown in Table 20. The median follow-up was 27.1 months (range 3.7 to 88.7 months) and median duration of exposure to TIBSOVO was 8.3 months (range 3.3 to 78.8 months).

For patients who achieved a CR, the median time to CR was 1.9 months (range, 1.0 to 5.6 months).

Among the 9 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 6 (67%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 9 patients who were independent of both RBC and platelet transfusions at baseline, 7 (78%) remained transfusion independent during any 56-day post-baseline period.

14.4 Locally Advanced or Metastatic Cholangiocarcinoma

The efficacy of TIBSOVO was evaluated in a randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-005, NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation whose disease had progressed following at least 1 but not more than 2 prior regimens, including at least one gemcitabine- or 5-FU-containing regimen. Patients were randomized to receive either TIBSOVO 500 mg orally once daily or matched placebo until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 or 2). Eligible patients who were randomized to placebo were allowed to cross over to receive TIBSOVO after documented radiographic disease progression. Patients with IDH1 mutations were selected using a central diagnostic next generation sequencing assay. Tumor imaging assessments were performed every 6 weeks for the first 8 assessments and every 8 weeks thereafter.

The major efficacy outcome measure was Progression Free Survival (PFS) as determined by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The median age was 62 years (range: 33 to 83); 63% were female; 57% were White, 12% Asian, 1.1% Black, 0.5% Native Hawaiian/Other Pacific Islander, 0.5% American Indian or Alaska Native, 28% race missing/not reported; and 37% had an ECOG performance status of 0 (37%) or 1 (62%). All patients received at least 1 prior line of systemic therapy and 47% received two prior lines. Most patients had intrahepatic cholangiocarcinoma (91%) at diagnosis and 92% had metastatic disease. Across both arms, 70% patients had an R132C mutation, 15% had an R132L mutation, 12% had an R132G mutation, 1.1% had an R132H mutation, and 1.6% had an R132S mutation.

The efficacy results are shown in Table 21 and Figure 2. The study demonstrated a statistically significant improvement in PFS.

Figure 2: Kaplan-Meier Plot of Progression-Free Survival per Independent Review Committee - Before Crossover (ITT)

How Supplied

250 mg tablet: Blue oval-shaped film-coated tablet debossed "IVO" on one side and "250" on the other side.

• 60-count bottles of 250 mg tablets with a desiccant canister (NDC 72694-617-60)

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Differentiation Syndrome in AML and MDS

Advise patients being treated with TIBSOVO of the risks of developing differentiation syndrome as early as 1 day after start of therapy and during the first 3 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, rash, decreased urinary output, low blood pressure, rapid weight gain, or swelling of their arms or legs, to their healthcare provider for further evaluation [see Boxed Warning and Warnings and Precautions (5.1)].

QTc Interval Prolongation

Inform patients of symptoms that may be indicative of significant QTc interval prolongation including dizziness, lightheadedness, and fainting. Advise patients to report these symptoms and the use of all medications to their healthcare provider [see Warnings and Precautions (5.2)].

Guillain-Barré Syndrome

Inform patients of symptoms that may be indicative of Guillain-Barré syndrome, including new signs or symptoms of motor and/or sensory neuropathy, such as weakness or tingling sensation in the legs, arms, or upper body, numbness and pain on one side or both sides of the body, changes to any sensory function, or burning or prickling sensation, or difficulty breathing. Advise patients to report these symptoms to their healthcare provider [see Warnings and Precautions (5.3)].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications, vitamins, and herbal products [see Drug Interactions (7)].

Tumor Lysis Syndrome

Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values [see Adverse Reactions (6.1)].

Gastrointestinal Adverse Reactions

Advise patients on the risks of experiencing gastrointestinal reactions such as diarrhea, nausea, mucositis, constipation, vomiting, decreased appetite, ascites and abdominal pain. Ask patients to report these events to their healthcare provider and advise patients how to manage them [see Adverse Reactions (6.1)].

Lactation

Advise women not to breastfeed during treatment with TIBSOVO and for 1 month after the last dose [see Use in Specific Populations (8.2)].

Dosing and Storage Instructions

• Advise patients to swallow tablets whole and to not split, crush, or chew TIBSOVO tablets.
• Advise patients to avoid taking TIBSOVO with a high-fat meal.
• Instruct patients that if a dose of TIBSOVO is vomited, not to take an additional dose, and wait until the next scheduled dose is due. If a dose of TIBSOVO is missed or not taken at the usual time, instruct patients to take the dose as soon as possible unless the next dose is due within 12 hours. Patients can return to the normal schedule the following day.
• Store TIBSOVO at room temperature from 20°C to 25°C (68°F to 77°F).
• Advise patients not to remove the desiccant canister from the bottle.