Vanflyta Product Monograph

Recent Major Label Changes

None at time of the most recent authorization.

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 3. Serious Warnings and Precautions Box ............................................................................ 4
4. 4.

   Dosage and Administration ............................................................................................. 5

   4.1. Dosing Considerations .............................................................................................. 5

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 5

   4.4. Administration .......................................................................................................... 8

   4.5. Missed Dose ............................................................................................................. 9

5. 5. Overdose ......................................................................................................................... 9
6. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 9
7. 7.

   Warnings and Precautions ............................................................................................. 10

   Carcinogenesis and Genotoxicity ........................................................................................ 10

   Cardiovascular .................................................................................................................... 10

   Reproductive Health ........................................................................................................... 11

   7.1. Special Populations ................................................................................................ 11

   7.1.1. Pregnancy ...................................................................................................... 11

   7.1.2. Breastfeeding ................................................................................................ 11

   7.1.3. Pediatrics ....................................................................................................... 12

   7.1.4. Geriatrics ....................................................................................................... 12

8. 8.

   Adverse Reactions ......................................................................................................... 12

   8.1. Adverse Reaction Overview .................................................................................... 12

   8.2. Clinical Trial Adverse Reactions .............................................................................. 13

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 15

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 16

9. 9.

   Drug Interactions ........................................................................................................... 17

   9.2. Drug Interactions Overview .................................................................................... 17

   9.3. Drug-Behaviour Interactions .................................................................................. 17

   9.4. Drug-Drug Interactions ........................................................................................... 17

   9.5. Drug-Food Interactions........................................................................................... 19

   9.6. Drug-Herb Interactions ........................................................................................... 20

   9.7. Drug-Laboratory Test Interactions ......................................................................... 20

10. 10.

    Clinical Pharmacology ................................................................................................... 20

    10.1. Mechanism of Action .............................................................................................. 20

    10.2. Pharmacodynamics ................................................................................................ 20

    10.3. Pharmacokinetics ................................................................................................... 20

11. 11. Storage, Stability, and Disposal ...................................................................................... 23

Part 2: Scientific Information ................................................................................................ 24

1. 13. Pharmaceutical Information .......................................................................................... 24
2. 14.

   Clinical Trials .................................................................................................................. 25

   14.1. Clinical Trials by Indication ..................................................................................... 25

3. 15. Microbiology ................................................................................................................. 28
4. 16. Non-Clinical Toxicology .................................................................................................. 29

Patient Medication Information ........................................................................................... 31

Part 1: Healthcare Professional Information

1. Indications

VANFLYTA (quizartinib) is indicated:

• in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by VANFLYTA maintenance monotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) positive.

  Improvement in overall survival has not been demonstrated for maintenance monotherapy following allogeneic hematopoietic stem cell transplantation (see 14.1 Clinical Trials by Indication).

  A validated test is required to confirm the FLT3-ITD status of AML.

1.1. Pediatrics

Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (>65 years): Evidence from clinical studies suggests that differences in safety were observed in the geriatric population (see 7.1.4 Geriatrics).

2. Contraindications

VANFLYTA is contraindicated in patients:

• with congenital long QT syndrome or with a history of ventricular arrhythmias or torsades de pointes (see 7 Warnings and Precautions, Cardiovascular).
• With severe uncorrected hypokalemia or hypomagnesemia (see 7 Warnings and Precautions, Cardiovascular).
• who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition and Packaging.

3. Serious Warnings and Precautions Box

• VANFLYTA can prolong the QT interval (see 10.2 Pharmacodynamics). Torsades de pointes, cardiac arrest, and sudden death have been reported in patients receiving VANFLYTA (see 7 Warnings and Precautions, Cardiovascular, and 8 Adverse Reactions). Electrocardiograms (ECGs) should be performed, and electrolyte abnormalities should be corrected before initiating VANFLYTA treatment. Do not initiate VANFLYTA therapy if the QT interval corrected by Fridericia’s formula (QTcF) is greater than 450 ms or in patients with severe hypokalemia, hypomagnesemia, or

  • long QT syndrome. Monitor ECGs and electrolyte levels during treatment. VANFLYTA dosage adjustment may be required in the event of QT prolongation. Reduce the VANFLYTA dose when used concomitantly with strong CYP3A inhibitors (see 2 Contraindications, 4.2 Recommended Dose and Dosage Adjustment and 7 Warnings and Precautions, Cardiovascular).

4. Dosage and Administration

4.1. Dosing Considerations

Select patients for the treatment of AML with VANFLYTA based on the presence of FLT3-ITD mutation (see 14.1 Clinical Trials by Indication).

VANFLYTA should be initiated only if QTcF is less than or equal to 450 ms (see 7 Warnings and Precautions, Cardiovascular).

During induction and consolidation, electrocardiograms (ECGs) should be performed prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated (see 7 Warnings and Precautions, Cardiovascular).

During maintenance, ECGs should be performed prior to initiation and then once weekly for the first month following dose initiation and escalation and thereafter as clinically indicated. The dose should be escalated only if QTcF is less than or equal to 450 ms (see Table 1 and 7 Warnings and Precautions, Cardiovascular).

Electrolyte abnormalities (hypokalemia and hypomagnesemia) should be corrected, and if possible, concomitant administration of drugs that prolong the QT interval should be avoided (see 7 Warnings and Precautions, Cardiovascular).

4.2. Recommended Dose and Dosage Adjustment

Treatment with VANFLYTA should be initiated by a physician experienced in the use of anticancer therapies.

Recommended Dose

VANFLYTA should be administered in combination with standard chemotherapy at a dose of 35.4 mg (2 x 17.7 mg) once daily for two weeks in each cycle of induction. For patients who achieved complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), VANFLYTA should be administered at 35.4 mg once daily for two weeks in each cycle of consolidation chemotherapy followed by VANFLYTA maintenance monotherapy initiated at 26.5 mg once daily. After two weeks the maintenance dose should be increased to 53 mg (2 x 26.5 mg) once daily if the QT interval corrected by Fridericia’s formula (QTcF) is less than or equal to 450 ms (see Table 2 and 7 Warnings and Precautions, Cardiovascular).

For additional dosing information, see Table 1, Table 2 and Table 3.

Table 1: VANFLYTA Dose Regimen

^a Patients can receive up to 2 cycles of induction.

^b Patients can receive up to 4 cycles of consolidation.

^c For 5 + 2 regimen as the second induction cycle, VANFLYTA will be started on Day 6.

See 14 Clinical Trials for Chemotherapy dosing during the QuANTUM-First study.

For patients who proceed to hematopoietic stem cell transplantation (HSCT), VANFLYTA should be stopped 7 days before the start of a conditioning regimen. VANFLYTA may be resumed after completion of the transplant based on white blood cell count (WBC) and at the discretion of the treating physician for patients with sufficient hematologic recovery and with less than or equal to Grade 2 graft-versus-host disease (GVHD), not requiring the initiation of new systemic GVHD therapy within 21 days, following the dosing recommendations described above.

Dose Modifications

The recommended dose modifications guidelines for adverse reactions are listed in Table 2.

Table 2: Recommended Dose Modifications for Adverse Reactions

Grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).

Table 3: Dose Adjustments for Adverse Reactions by Phase during Treatment with VANFLYTA

Concomitant use with strong cytochrome P450 enzyme (CYP3A) inhibitors may increase quizartinib exposure. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the dose of VANFLYTA as shown in Table 4. After discontinuation of the strong CYP3A inhibitor, resume VANFLYTA at the original dose (see 9.4 Drug-Drug Interactions).

The recommended dose reductions when VANFLYTA is used concomitantly with strong CYP3A inhibitors are listed in Table 4.

Table 4: Dosage Adjustments for Concomitant Use with Strong CYP3A Inhibitors

Treatment with VANFLYTA should be interrupted in patients receiving the 17.7 mg dose and requiring treatment with a strong CYP3A inhibitor.

Special Populations

Pediatrics (≤ 18 years)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥ 65 years)

No dose adjustment of VANFLYTA is required in patients aged 65 years or older (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics, Special Populations and Conditions).

Renal Impairment

No dose adjustment is recommended for patients with mild or moderate renal impairment.

VANFLYTA is not recommended for use in patients with severe renal impairment (creatinine clearance [CLcr] <30 mL/min, estimated by Cockcroft-Gault) as safety and efficacy have not been evaluated in this population (see 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

Hepatic Impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment.

VANFLYTA is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C or total bilirubin >3 times ULN and any value for AST) as safety and efficacy have not been evaluated in this population (see 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic Insufficiency).

4.4. Administration

VANFLYTA should be taken orally at approximately the same time each day and may be taken with or without food. Swallow tablets whole. Do not cut, crush, or chew the tablets.

4.5. Missed Dose

Missed Dose or Vomiting

If a dose of VANFLYTA is missed or not taken at the usual time, the patient should take the dose as soon as possible on the same day and return to the usual schedule the following day. The patient should not take two doses on the same day.

If the patient vomits after taking VANFLYTA, the patient should not take an additional dose that day. The patient should take the next dose the following day at the usual time.

5. Overdose

There is no known antidote for overdoses of VANFLYTA. In the event of an overdose, interrupt treatment, perform an ECG to monitor for QT interval prolongation (see 4.2 Recommended Dose and Dosage Adjustment and 7 Warnings and Precautions, Cardiovascular), and give appropriate supportive measures.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 5: Dosage Forms, Strengths, Composition and Packaging

Description

VANFLYTA 17.7 mg tablets

A white, round, tablet, debossed with “DSC511.” Each tablet contains 17.7 mg quizartinib (as quizartinib hydrochloride).

VANFLYTA 26.5 mg tablets

A yellow, round, tablet, debossed with “DSC512.” Each tablet contains 26.5 mg quizartinib (as quizartinib hydrochloride).

Packaging:

Aluminium blisters with 14 tablets per blister card in a carton containing 1, 2 or 4 blister cards.

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

See 16 Non-Clinical Toxicology.

Cardiovascular

QT Interval Prolongation, Torsades de Pointes, and Cardiac Arrest

VANFLYTA prolongs the QT interval in a dose- and concentration-dependent manner (see 10.2 Pharmacodynamics). Torsades de pointes, cardiac arrest, and sudden death have been reported in patients receiving VANFLYTA (see 8 Adverse Reactions). The quizartinib development program excluded patients with a QTcF ≥450 ms or other factors that increased the risk of QT prolongation or arrhythmic events (e.g., New York Heart Association Class III or IV congestive heart failure, hypokalemia, family history of long QT interval syndrome, history of second- or third-degree heart block, myocardial infarction within 6 months, uncontrolled angina pectoris, uncontrolled hypertension).

VANFLYTA is contraindicated in patients with congenital long QT syndrome, with a history of ventricular arrhythmias or torsades de pointes, or with severe uncorrected hypokalemia or hypomagnesemia (see 2 Contraindications). VANFLYTA should be used with caution in patients who are at risk of developing QT interval prolongation, including patients with uncontrolled or significant cardiovascular disease, and patients receiving concomitant drugs known to prolong the QT interval.

ECGs should be performed, and electrolyte abnormalities should be corrected prior to initiation of treatment. Do not start treatment with VANFLYTA if the QTcF interval is greater than 450 ms. Electrolytes should be maintained in the normal range (see 4.1 Dosing Considerations).

During induction and consolidation, ECGs should be performed prior to initiation and then once weekly during VANFLYTA treatment or more frequently as clinically indicated.

During maintenance, ECGs should be performed prior to initiation and then once weekly for the first month following dose initiation and escalation and thereafter as clinically indicated. The maintenance starting dose should not be escalated if the QTcF interval is greater than 450 ms (see Table 1).

Permanently discontinue VANFLYTA in patients who develop QT interval prolongation with signs or symptoms of life-threatening arrhythmia (see 4.2 Recommended Dose and Dosage Adjustment).

ECG monitoring of the QT interval should be performed more frequently in patients who are at significant risk of developing QT interval prolongation and torsades de pointes.

Monitoring and correction of hypokalemia and hypomagnesemia should be performed prior to and during treatment with VANFLYTA. More frequent monitoring of electrolytes and ECGs should be performed in patients who experience diarrhea or vomiting.

ECG Monitoring with QT Interval Prolonging Medicinal Products

Patients should be monitored more frequently with ECGs if coadministration of VANFLYTA with medicinal products known to prolong the QT interval is required. Examples of QT prolonging drugs include but are not limited to antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine, and tacrolimus.

Concomitant Use with Strong CYP3A Inhibitors

Concomitant use with strong CYP3A inhibitors may increase quizartinib exposure, and therefore, the dose of VANFLYTA should be reduced (see 4.2 Recommended Dose and Dosage Adjustment and 9.4 Drug-Drug Interactions).

Reproductive Health

• Fertility

There are no human data on the effect of VANFLYTA on fertility. Based on findings in animals, female and male fertility may be impaired with treatment with VANFLYTA (see 16 Non-Clinical Toxicology).

7.1. Special Populations

7.1.1. Pregnancy

There are no data on the use of quizartinib in pregnant women. Based on findings in animals, VANFLYTA may cause embryo-fetal toxicity when administered to pregnant women (see 16 Non-Clinical Toxicology).

VANFLYTA should not be used during pregnancy. Pregnant women should be advised of the potential risk to the fetus.

Women of childbearing potential should undergo pregnancy testing before starting treatment with VANFLYTA.

Based on findings in animals, VANFLYTA may cause embryo-fetal harm when administered to a pregnant woman (see 16 Non-clinical Toxicology). Advise pregnant women of the potential risk to the fetus. Advise women of reproductive potential to use effective contraception during treatment with VANFLYTA and for at least 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VANFLYTA and for at least 4 months after the last dose.

7.1.2. Breastfeeding

It is unknown whether quizartinib or its active metabolites are excreted in human milk. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with VANFLYTA and for at least 5 weeks after the last dose.

7.1.3. Pediatrics

Pediatrics (< 18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Of the 533 patients with newly diagnosed AML in the QuANTUM-First study 134 (25.1%) were 65 years of age and older, while 2 (0.4%) were 75 years of age. A higher incidence of fatal infections was reported in patients 65 years of age and older, compared to younger patients (13% vs. 5.7%), especially in the early treatment period. Discontinuations were reported in 29% of patients 65 years of age and older, and in 16.4% of younger patients.

Clinical studies of VANFLYTA did not include sufficient numbers of patients 75 years of age and older to determine whether they respond differently from younger adult patients.

8. Adverse Reactions

8.1. Adverse Reaction Overview

In QuANTUM-First, the phase III, randomized, placebo-controlled trial of VANFLYTA in patients with newly diagnosed FLT3-ITD positive AML, the most common adverse reactions (incidence ≥20%) in the VANFLYTA arm were febrile neutropenia, diarrhea, nausea, sepsis, abdominal pain, neutropenia, headache and vomiting. The most common Grade 3 or 4 adverse reactions (incidence ≥5%) were febrile neutropenia, sepsis, neutropenia, thrombocytopenia, fungal infections, and anemia.

The most common serious adverse reactions (incidence ≥2%) in the VANFLYTA arm were febrile neutropenia (11%), neutropenia (3.0%), fungal infections (2.3%) and herpes infections (2.3%). Adverse reactions with a fatal outcome were sepsis (5.0%), fungal infections (0.8%) and cardiac arrest (0.4%).

The most common adverse reactions (incidence ≥2%) associated with dose interruption of VANFLYTA were neutropenia (10.6%), thrombocytopenia (4.5%) and electrocardiogram QT prolonged (2.6%). The most common adverse reactions (incidence ≥2%) associated with dose reduction of VANFLYTA were neutropenia (9.1%), thrombocytopenia (4.5%) and electrocardiogram QT prolonged (3.8%).

The most common adverse reactions (incidence ≥1%) associated with permanent discontinuation of VANFLYTA were sepsis (5%) and thrombocytopenia (1.1%).

Safety Profile During Maintenance Monotherapy

During the maintenance monotherapy phase of QuANTUM-First, the most common adverse reactions in the VANFLYTA arm were neutrophil count decreased (87.9%), platelet count decreased (72.4%), hemoglobin decreased (55.2%), alanine aminotransferase increased (49.1%), upper respiratory tract infections (27.6%), nausea (23.3%) and diarrhea (20.7%). The most frequent Grade 3 or 4 adverse reactions with VANFLYTA were neutrophil count decreased (71.6%), platelet count decreased (24.1%) and hemoglobin decreased (18.1%).

The most common serious adverse reactions in the VANFLYTA arm were herpes infections (3.4%), neutropenia (2.6%), upper respiratory tract infections (1.7%) and vomiting (1.7%). No fatal adverse reactions occurred during maintenance.

The most common adverse reactions associated with dose interruption of VANFLYTA were neutropenia (24.1%), thrombocytopenia (10.3%) and electrocardiogram QT prolonged (4.3%). The most common adverse reactions associated with dose reduction of VANFLYTA were neutropenia (20.7%), thrombocytopenia (10.3%) and electrocardiogram QT prolonged (5.2%). The most common adverse reactions associated with permanent discontinuation of VANFLYTA were thrombocytopenia (2.6%), nausea, neutropenia and decreased appetite (1.7% each).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety of VANFLYTA was investigated in QuANTUM-First, a randomized, double-blind, placebo-controlled trial in adult patients with newly diagnosed FLT3-ITD positive AML. Patients were treated with VANFLYTA (N=265) or placebo (N=268) in combination with standard chemotherapy, followed by VANFLYTA maintenance monotherapy (see 14 Clinical Trials). The overall median duration of therapy was 10.7 weeks (range: 0.1 to 184.1) for patients in the VANFLYTA arm versus 9.5 weeks (range: 0.4 to 181.9) for patients in the placebo arm. In QuANTUM-First, 116 (43.8%) of patients in the VANFLYTA arm and 92 (34.3%) patients in the placebo arm entered the maintenance monotherapy treatment phase. The median duration of therapy for maintenance was 67.4 weeks (range: 0.4 to 167.0) for patients in the VANFLYTA arm versus 67.7 weeks (range: 0.3 to 167.4) for patients in the placebo arm.

Table 6 presents adverse reactions reported in ≥10% of VANFLYTA-treated patients in the QuANTUM-First Clinical Study.

Table 6: Adverse Reactions Reported in ≥10% of VANFLYTA-Treated Patients in Quantum-First Study (Safety Analysis Set)

Standard Chemotherapy = cytarabine (cytosine arabinoside) and anthracycline (daunorubicin or idarubicin)

^a Including fatalities

^b Includes neutropenia and neutrophil count decreased.

^c Includes thrombocytopenia and platelet count decreased.

^d Diarrhea includes diarrhea and diarrhea hemorrhagic.

^e Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower and gastrointestinal pain.

^f Edema includes edema peripheral, face edema, edema, fluid overload, generalized edema, peripheral swelling, localized edema and face swelling.

^g Sepsis includes acinetobacter infection, bacteremia, bacterial sepsis, corynebacterium bacteremia, device related bacteremia, device related sepsis, enterobacter sepsis, enterococcal bacteremia, enterococcal sepsis, escherichia bacteremia, escherichia sepsis, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal bacteremia, pulmonary sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal infection, staphylococcal sepsis, stenotrophomonas sepsis, streptococcal sepsis, and streptococcal bacteremia.

^h Upper respiratory tract infections include upper respiratory tract infection, nasopharyngitis, sinusitis, rhinitis, tonsillitis, laryngopharyngitis, pharyngitis bacterial, pharyngotonsillitis, viral pharyngitis and acute sinusitis.

ⁱ Fungal infections include oral candidiasis, bronchopulmonary aspergillosis, fungal infection, vulvovaginal candidiasis, aspergillus infection, lower respiratory tract infection fungal, oral fungal infection, candida infection, fungal skin infection, mucormycosis, oropharyngeal candidiasis, aspergillosis oral, hepatic infection fungal, hepatosplenic candidiasis, onychomycosis, fungemia, systemic candida and systemic mycosis.

^j Herpes infections include oral herpes, herpes zoster, herpes virus infections, herpes simplex, human herpesvirus 6 infection, genital herpes and herpes dermatitis.

^k Headache includes headache, tension headache and migraine.

^I Electrocardiogram QT prolonged includes electrocardiogram QT prolonged and electrocardiogram QT interval abnormal.

Cardiac Disorders

VANFLYTA prolongs the QT interval on ECG. Any grade QT interval prolongation treatment emergent adverse events were reported in 14.0% of VANFLYTA-treated patients. Three percent of patients experienced events of Grade 3 or higher severity. QT prolongation was associated with dose reduction in 10 (3.8%) patients, dose interruption in 7 (2.6%) patients, and discontinuation in 2 (0.8%) patients. QTcF >500 ms occurred in 2.3% of patients based on central review of ECG data. Two (0.8%) patients treated with VANFLYTA experienced cardiac arrest with recorded ventricular fibrillation, one with a fatal outcome, both in the setting of severe hypokalemia.

8.3. Less Common Clinical Trial Adverse Reactions

Less common adverse reactions reported in <10% of patients treated with VANFLYTA in QuANTUM-First are shown below.

Blood and lymphatic system disorders: pancytopenia

Cardiac disorders: cardiac arrest; ventricular fibrillation

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Table 7: New or Worsening Laboratory Abnormalities (in ≥10% of Subjects with ≥2% Difference for Quizartinib Compared to Placebo) in QuANTUM-First Study (Safety Analysis Set)

^a Terms based on laboratory data.

The denominator used to calculate the rate varied from 199 to 260 in VANFLYTA + Chemotherapy and from 187 to 267 in PLACEBO + Chemotherapy based on the number of patients with a baseline value and at least one post-treatment value except for Cholesterol high (CHOL) which is only collected at Screening and end of treatment with 83 as the denominator in VANFLYTA + Chemotherapy and 91 as the denominator in PLACEBO + Chemotherapy.

Table 8: New or Worsened QTcF Prolongation in QuANTUM-First Study (Safety Analysis Set)

Note: Based on central assessment of ECG. “New” implies a newly occurring ECG abnormality, which is defined as an abnormal postbaseline ECG finding that is not present at baseline.

ms = millisecond

9. Drug Interactions

9.2. Drug Interactions Overview

Quizartinib and its active metabolite AC886 are primarily metabolized by CYP3A in vitro.

Concomitant administration of a strong CYP3A inhibitor with VANFLYTA requires a dose reduction (see 4.2 Recommended Dose and Dosage Adjustment, Table 4). Strong and moderate CYP3A inducers should be avoided (see 9.4 Drug-Drug Interactions, Table 9).

Co-administration of VANFLYTA with other medicinal products that prolong the QT interval may further increase the incidence of QT prolongation (see 9.4 Drug-Drug Interactions, Table 9).

Quizartinib is an inhibitor of Breast Cancer Resistance Protein (BCRP) and may increase the exposure of drugs that are sensitive BCRP substrates (see 9.4 Drug-Drug Interactions, Table 9).

9.3. Drug-Behaviour Interactions

The interaction of VANFLYTA with individual behavioural risks (e.g. cigarette smoking, cannabis use, and/or alcohol consumption) has not been studied.

9.4. Drug-Drug Interactions

The drugs listed in Table 9 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 9: Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical.

In vitro Studies:

Quizartinib is a substrate of P-gp, but not a substrate of BCRP, OATP1B1, OATP1B3, OCT1, OAT2, MATE1, or MRP2. AC886 is a substrate of BCRP but not a substrate of OATP1B1, OATP1B3, MATE1, or MRP2.

Quizartinib is not an inducer of CYP3A4, CYP1A2, or CYP2B6. Quizartinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. AC886 is not an inducer of CYP3A4, CYP1A2, or CYP2B6. AC886 is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2C19, or CYP3A4.

9.5. Drug-Food Interactions

VANFLYTA can be administered with or without food (see 10.3 Pharmacokinetics).

Grapefruit, grapefruit juice and other foods that are known to affect CYP3A activity should be avoided during treatment with VANFLYTA.

9.6. Drug-Herb Interactions

Drug-herb interactions have not been studied. St. John’s wort (Hypericum perforatum) is an inducer of CYP3A that may decrease quizartinib plasma concentrations and should be avoided.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Quizartinib is a small molecule inhibitor of the FMS-related receptor tyrosine kinase (FLT3). Quizartinib and its major circulating active metabolite AC886 bind to the adenosine triphosphate (ATP) binding pocket of FLT3 with comparable affinity. Quizartinib and AC886 inhibit FLT3 kinase activity, preventing autophosphorylation of the receptor, thereby inhibiting further downstream FLT3 receptor signaling and blocking FLT3-ITD-dependent cell proliferation.

10.2. Pharmacodynamics

Cardiac Electrophysiology

The exposure-response analysis of QuANTUM-First predicted a concentration-dependent QTcF interval prolongation of 24.1 ms (upper bound of two-sided 90% CI: 26.6 ms) at the steady-state C_max of quizartinib (53 mg) during maintenance therapy.

10.3. Pharmacokinetics

The pharmacokinetics of quizartinib and its active metabolite AC886 were evaluated in healthy adult volunteers (single dose) and in patients with newly diagnosed AML (steady state).

Steady state quizartinib concentrations were achieved at day 15 following once daily dosage in patients with AML. Quizartinib exhibited dose proportional pharmacokinetics (AUC and C_max) in the dose range of 26.5 mg to 79.5 mg in healthy subjects and 17.7 mg to 53 mg in AML patients.

Table 10: Treatment Phase Dependent Quizartinib and Major Metabolite AC886 Pharmacokinetic Parameters in Patients with AML (QuANTUM-First)

^a Generated by Population Pharmacokinetic Model

^b Reported as geometric mean (%CV)

^c Reported as median (min, max).

Absorption

The absolute bioavailability of quizartinib from the tablet formulation was 71% (±7%). After oral administration under fasted conditions, time to peak concentration (median T_max) of quizartinib and AC886 measured post dose was approximately 4 hours (range 2 to 8 hours) and 5 to 6 hours (range 4 to 120 hours), respectively, in healthy subjects.

Food effect

The extent (AUC_T) and rate (C_max) of quizartinib absorption were not significantly affected when VANFLYTA was co-administered with food. The T_max was delayed by 2 hours. VANFLYTA can be administered with or without food.

Distribution

The geometric mean (%CV) volume of distribution at steady state (Vss) of quizartinib in healthy subjects was estimated to be 275 L (17%).

In vitro binding of quizartinib and AC886 to human plasma proteins is greater than or equal to 99%.

Quizartinib and AC886 partition into red blood cells with blood-to-plasma ratios ranging from 0.79-1.30 and 1.36-3.19, respectively, in the concentration range of 10 to 1,000 ng/mL studied in vitro.

Metabolism

Quizartinib is primarily metabolized by CYP3A in vitro via oxidative pathways which produces the active metabolite AC886, which is then further metabolized by CYP3A.

Elimination

The geometric mean (%CV) total body clearance (CL) of quizartinib in healthy subjects was estimated to be 2.23 (29%) L/hour.

The mean standard deviation (SD) effective half-lives (t_1/2) for quizartinib and AC886 are 81 hours (±73) and 136 hours (±113), respectively, in patients with newly diagnosed AML.

Following a single radiolabeled dose of quizartinib 53 mg to healthy subjects, 76.3% of the total radioactivity was recovered in feces (4% unchanged) and 1.64% in urine.

Special populations and conditions

• Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. No results are currently available from ongoing studies to investigate the pharmacokinetics of quizartinib in pediatric patients.

• Geriatrics

No clinically significant differences in quizartinib pharmacokinetics were noted between patients 65 years of age and older and those under 65 years based on a population pharmacokinetic analysis.

• Sex

No clinically significant differences in quizartinib pharmacokinetics were noted between male and female patients based on a population pharmacokinetic analysis.

• Ethnic origin

No clinically significant differences in quizartinib pharmacokinetics were noted based on the covariate of race (White, Asian, Black or African American) according to population pharmacokinetic analysis.

• Hepatic Insufficiency

In two single dose (26.5 mg) phase 1 studies, the pharmacokinetics of quizartinib and AC886 were assessed in subjects with mild hepatic impairment (Child Pugh Class A) or moderate hepatic impairment (Child Pugh Class B or total bilirubin at >1.5 to 3 times ULN and any value for AST) and compared to subjects with normal hepatic function. The exposures (C_max and AUC_inf) of quizartinib, aggregate quizartinib and AC886 were relatively similar (≤30% difference) across all groups. Population pharmacokinetic analysis including mostly subjects with normal and mild hepatic impairment (total bilirubin ≤ ULN and AST >ULN or total bilirubin >1 to 1.5 times ULN and any value for AST) showed that hepatic function did not affect quizartinib and AC886 clearance. Therefore, mild and moderate hepatic impairment did not have a clinically meaningful effect on quizartinib and AC886 exposure. No dose adjustment is recommended in patients with mild or moderate hepatic impairment.

Patients with severe hepatic impairment (Child Pugh Class C or total bilirubin >3 times ULN and any value for AST) were not included in the clinical studies, and therefore, VANFLYTA is not recommended for use in these patients.

• Renal Insufficiency

A population pharmacokinetic analysis in AML patients with mild to moderate renal impairment (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) showed that renal function did not affect quizartinib and AC886 clearance. Therefore, mild and moderate renal impairment did not have a clinically meaningful effect on quizartinib and AC886 exposure. No dose adjustment is recommended in patients with mild or moderate renal impairment.

Patients with severe renal impairment (CLcr <30 mL/min) were not included in the clinical trials, and therefore, VANFLYTA is not recommended for use in these patients.

• Obesity

No clinically significant differences in quizartinib pharmacokinetics were noted based on body weight (range 37 to 153 kg) according to population pharmacokinetic analysis.

1. 11. Storage, Stability, and Disposal

Store VANFLYTA at room temperature (15°C to 30°C). Keep out of the reach and sight of children.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: Quizartinib hydrochloride

Chemical name: 1-(5-tert-butyl-1,2-oxazol-3-yl)-3-(4-{7-[2-(morpholin-4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea dihydrochloride

Molecular formula and molecular mass: C₂₉H₃₂N₆O₄S•2 HCl

633.59 (as quizartinib dihydrochloride)

560.67 (as quizartinib free base)

Structural formula:

Physicochemical properties: Quizartinib dihydrochloride is a white to off-white solid with a molecular weight of 633.6 for the salt and 560.7 for the free base. The aqueous solubility of quizartinib dihydrochloride (pKa 4.75 and 3.16) decreases with increasing pH. It is very slightly soluble at pH 1, and practically insoluble or insoluble at pH 2 and higher. Quizartinib dihydrochloride is very slightly soluble in ethanol.

14. Clinical Trials

14.1. Clinical Trials by Indication

Newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML)

Table 11: Summary of Patient Demographics in QuANTUM-First in Patients with Newly Diagnosed FLT3-ITD positive AML

The efficacy and safety of VANFLYTA versus placebo was investigated in a randomized, double-blind, placebo controlled, phase 3 study (QuANTUM-First). The study enrolled 539 adult patients between 20 and 75 years of age who were newly diagnosed with FLT3-ITD positive AML. The FLT3-ITD status was determined prospectively by a clinical study assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx FLT3 Mutation Assay. Patients were stratified by age (<60 versus ≥60 years), white blood cell count at diagnosis (<40x10⁹/L versus ≥40x10⁹/L), and region (North America, Europe versus Asia, other regions). They were randomized 1:1 to receive VANFLYTA 35.4 mg once daily (n=268) or placebo (n=271) for two weeks in each cycle in combination with standard chemotherapy (induction followed by consolidation for responding patients) followed by maintenance monotherapy with VANFLYTA (26.5 mg once daily for two weeks and 53 mg once daily thereafter) or placebo for up to 36 cycles (28 days/cycle).

Patients received up to 2 cycles of induction chemotherapy (either daunorubicin [60 mg/m²/day IV on days 1, 2 and 3] or idarubicin [12 mg/m²/day IV on days 1, 2 and 3] with cytarabine [100 mg/m²/day or 200 mg/m²/day allowed if institutional or local standard, IV infusion for 7 days]), followed by post remission therapy which consisted of up to 4 cycles of consolidation chemotherapy and/or HSCT. Consolidation chemotherapy consisted of cytarabine 3.0 g/m² for patients less than 60 years old and 1.5 g/m² for patients greater than or equal to 60 years old, administered every 12 hours by IV infusion on days 1, 3 and 5. Patients who proceeded to HSCT stopped receiving study treatment 7 days before the start of a conditioning regimen and initiated maintenance therapy after recovery from the HSCT.

The two randomized treatment groups were generally balanced with respect to baseline demographics, disease characteristics and stratification factors (see Table 12).

Table 12: Demographics and Baseline Characteristics in QuANTUM-First Study (Intent-to-Treat Population)

AML = acute myeloid leukemia; ECOG = Eastern Cooperative Oncology Group; FLT3 = FMS like tyrosine kinase 3; ITD = internal tandem duplications; NPM1 = nucleophosmin 1; VAF = variant allelic frequency; WBC = white blood cells; WHO = World Health Organization.

The baseline value is defined as the last non missing value before initial administration of study drug.

^a Age in years is calculated using the birth date and informed consent date.

Study Results

The primary efficacy measure was overall survival (OS) defined as the time from randomization until death from any cause. The median follow-up time of the study was 39.2 months.

The study demonstrated a statistically significant improvement in overall survival with a 22.4% risk reduction of death for VANFLYTA versus placebo (Figure 1).

Figure 1: Kaplan-Meier Curve for Overall Survival in QuANTUM-First

Complete remission (CR) was measured from the date of first CR to the date of relapse or death from any cause. The CR rate in the VANFLYTA arm was 54.9% (95% CI: 48.7, 60.9) with a median duration of CR of 38.6 months (95% CI: 21.9, NE) and the CR rate in the placebo arm was 55.4% (95% CI: 49.2, 61.4) with a median duration of CR of 12.4 months (95% CI: 8.8, 22.7).

In an exploratory subgroup analysis of the 89 (43%) patients who received maintenance therapy with VANFLYTA or placebo following consolidation chemotherapy without HSCT, the OS HR was 0.40 (95% CI: 0.19-0.84). Of 119 (57%) patients who received maintenance therapy with VANFLYTA or placebo following HSCT, the OS HR was 1.62 (95% CI: 0.62, 4.22).

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology

In repeat dose toxicity studies conducted in rats, dogs and monkeys, principal organs of toxicity were hematopoietic and lymphoid organs. Additional toxicities were observed in the liver, kidneys and reproductive organs.

In 13-week repeat-dose studies, quizartinib was administered orally at doses of 1, 3 and 10 mg/kg/day in the rat, 1, 5 and 15 mg/kg/day in the dog and 3, 6 and 12 mg/kg/day in the monkey, followed by a 4-week recovery period.

Hematopoietic organ toxicities were observed in all species and manifested in decreased red blood cells (RBC) and RBC parameters, decreased reticulocytes and white blood cells (WBC), correlating with hematopoietic hypocellularity in the bone marrow and lymphoid atrophy/necrosis in the thymus; in the spleen, extramedullary hematopoiesis and pigment deposition (rats, dogs) and lymphoid atrophy (monkeys) were also observed. These changes were mostly reversed at the end of the recovery period. Liver toxicity included increased aminotransferases (mostly reversed after recovery) in all species, hepatocellular vacuolation and necrosis (dogs, monkeys), birefringent crystal deposition, fibrosis, inflammation, reactive sinusoidal lining cells and bile duct hyperplasia in dogs; these changes were partially reversed after the recovery period. Kidney toxicity included tubular vacuolation and birefringent crystal deposition (rats) and tubular basophilia (rats, dogs) that were partially reversed following recovery. Clinical signs including reduced appetite/body weight, hunched posture, dehydration and uncoordination were observed in monkeys at the high dose. In dogs and monkeys, these changes were observed at exposures lower than the recommended human dose (RHD) based on AUC, while in the rat they were observed at exposures higher than the RHD. The no observed adverse effect levels (NOAEL) were considered to be 3 mg/kg/day in the rat, 5 mg/kg/day in the dog and 3 mg/kg/day in the monkey, corresponding to 1.19, 0.39 and 0.07 times the RHD based on AUC for rats, dogs and monkeys, respectively.

In vitro and Animal Safety Pharmacology Studies

In cardiovascular studies conducted in cynomolgus monkeys, quizartinib resulted in QT prolongation at doses approximately 2 times the RHD of 53 mg/day based on C_max. In in vitro studies, quizartinib primarily inhibited the slowly activating component of delayed rectifier potassium currents (IKs).

Genotoxicity

In genotoxicity studies, quizartinib was mutagenic in a bacterial reverse mutation assay, but not in a mammalian cell mutation assay (mouse lymphoma thymidine kinase) or in an in vivo transgenic rodent mutation assay. Quizartinib was not clastogenic in an in vitro chromosome aberration assay in peripheral blood lymphocytes and was not clastogenic or aneugenic in the rat bone marrow micronucleus assay after a single dose, but produced equivocal results following 28 days administration.

Carcinogenicity

No carcinogenicity studies were conducted with quizartinib.

Reproductive and developmental toxicology

In embryo-fetal reproductive toxicity studies, pregnant rats were administered oral doses of quizartinib during the period of organogenesis. Fetotoxicity (lower fetal weights, effects on skeletal ossification) and teratogenicity (fetal abnormalities including edema) were observed at 6 mg/kg/day (approximately 3 times the RHD of 53 mg/day based on AUC). At doses >10 mg/kg/day, embryo-fetal lethality and increased post-implantation loss were observed. Maternal toxicity was evident at >10 mg/kg/day by decreased body weight gains and lower food consumption and at 20 mg/kg/day by adverse clinical signs. Based on maternal toxicity and fetal effects, the NOAEL was considered to be 6 and 2 mg/kg/day, corresponding to approximately 2.75 and 0.43 times the RHD of 53 mg/day based on AUC, respectively.

Fertility studies in animals have not been conducted with quizartinib. However, adverse findings in male and female reproductive systems were observed in repeat dose toxicity studies in rats and monkeys. In female rats, ovarian cysts and vaginal mucosal modifications were observed at 10 mg/kg/day (approximately 8.41 times the RHD of 53 mg/day based on AUC). Findings in female monkeys included atrophy of the uterus, ovary, and vagina observed at ≥6 mg/kg/day (approximately 0.24 times the RHD). In male rats, decreased testis weight, testicular seminiferous tubular degeneration and failure of sperm release were observed at 10 mg/kg/day (approximately 6.41 times the RHD). Findings in male monkeys included germ cell depletion in the testes observed at ≥6 mg/kg/day (approximately 0.40 times the RHD). After a four-week recovery period, all these findings except the vaginal mucosal modifications in the female rats were reversed.

Special Toxicology

In local tolerance studies in rabbits, quizartinib was considered a mild irritant of the ocular tissue and a slight irritant of the skin. In in vitro studies on 3T3 cells, quizartinib was found to have low potential for phototoxicity.