Quizartinib

Quizartinib inhibits FLT3, a receptor tyrosine kinase. In FLT3-ITD-positive acute myeloid leukaemia (ITD stands for internal tandem duplication), the proliferation of leukaemic cells depends on signalling from the mutated receptor, and quizartinib blocks that signalling.

Mechanism of Action

• FLT3 inhibition: quizartinib and its major active metabolite AC886 bind competitively, with high affinity, to the ATP-binding pocket of FLT3.
• Signalling blocked: both inhibit FLT3 kinase activity and prevent autophosphorylation of the receptor, which stops downstream FLT3 signalling and blocks the proliferation of FLT3-ITD-dependent cells.
• Cardiac electrophysiology: in vitro studies show that quizartinib is a predominant inhibitor of the slow delayed rectifier potassium current (IKs). In the QuANTUM-First study, exposure–response analysis predicted a QTcF prolongation of 24.1 ms (upper bound of the two-sided 90% confidence interval 26.6 ms) at the steady-state peak concentration reached with 53 mg during maintenance therapy.
• Clinical study: QuANTUM-First was a randomised, double-blind, placebo-controlled phase III study in 539 adults aged 18–75 years with newly diagnosed FLT3-ITD-positive AML. Patients received quizartinib or placebo (1:1) together with standard chemotherapy, then single-agent maintenance for up to 36 cycles.

Pharmacokinetics

• Absorption: the absolute bioavailability of the tablet is 71%. In healthy subjects under fasting conditions, peak concentrations occur after a median of about 4 hours for quizartinib (range 2–8 hours) and 5–6 hours for AC886 (range 4–120 hours). Food has no clinically relevant effect (peak concentration lower by 1.09-fold, AUC higher by 1.08-fold, peak delayed by two hours). In patients at the 53 mg maintenance dose, steady-state peak concentrations are about 529 ng/mL for quizartinib and 262 ng/mL for AC886.
• Distribution: both bind to plasma proteins by 99% or more in vitro. The volume of distribution of quizartinib in healthy subjects is about 275 L. The blood-to-plasma ratio depends on concentration; at clinically relevant concentrations it is about 1.3 for quizartinib and 2.8 for AC886.
• Metabolism: mainly by CYP3A (oxidation). AC886 is formed and further metabolised by CYP3A4/5.
• Elimination: effective half-lives during maintenance therapy are about 81 hours for quizartinib and 136 hours for AC886. After a single radiolabelled dose in healthy subjects, about 76% of the radioactivity was recovered in faeces (4% as unchanged quizartinib) and about 1.6% in urine. Total body clearance was about 2.2 L/hour.
• Special populations: no dose adjustment is needed in the elderly or in mild or moderate hepatic or renal impairment; quizartinib is not recommended in severe hepatic or renal impairment (see Administration and Dosage).

• Newly diagnosed AML: in combination with standard cytarabine and anthracycline induction and standard cytarabine consolidation chemotherapy, followed by single-agent quizartinib maintenance therapy, for adults with newly diagnosed acute myeloid leukaemia (AML) that is FLT3-ITD positive.
• Patient selection: FLT3-ITD-positive status must be confirmed before treatment with a CE-marked in vitro diagnostic test or, if none is available, another validated test.

• Hypersensitivity to quizartinib or to any of the excipients.
• Congenital long QT syndrome.
• Breast-feeding.

In the QuANTUM-First study, the most common adverse reactions were increased alanine aminotransferase (58.9%), decreased platelet count (40.0%), decreased haemoglobin (37.4%), diarrhoea (37.0%), nausea (34.0%), abdominal pain (29.4%), headache (27.5%), vomiting (24.5%) and decreased neutrophil count (21.9%). The most common grade 3 or 4 reactions were decreased platelet count (40%), decreased haemoglobin (35.5%), decreased neutrophil count (21.5%), increased alanine aminotransferase (12.1%), bacteraemia (7.2%) and fungal infections (5.7%).

Very common (≥1/10): upper respiratory tract infections, fungal infections, herpes infections, bacteraemia, thrombocytopenia, anaemia, neutropenia, decreased appetite, headache, epistaxis, diarrhoea, nausea, abdominal pain, vomiting, dyspepsia, increased alanine aminotransferase, oedema, prolonged electrocardiogram QT interval.

Common (≥1/100 to <1/10): pancytopenia.

Uncommon (≥1/1,000 to <1/100): cardiac arrest, ventricular fibrillation.

Thrombocytopenia, anaemia, neutropenia and increased alanine aminotransferase are terms based on laboratory data. The most common serious reactions were neutropenia (3.0%), fungal infections (2.3%) and herpes infections (2.3%); reactions with a fatal outcome were fungal infections (0.8%) and cardiac arrest (0.4%).

QT prolongation was reported in 14.0% of patients (grade 3 or higher in 3.0%), and a QTcF above 500 ms was seen in 2.3% on central ECG review. Two patients (0.8%) had cardiac arrest with recorded ventricular fibrillation, one of them fatal, both with severe hypokalaemia. The most common reasons for dose interruption were neutropenia (10.6%), thrombocytopenia (4.5%) and QT prolongation (2.6%); for dose reduction, neutropenia (9.1%), thrombocytopenia (4.5%) and QT prolongation (3.8%); and for permanent discontinuation, thrombocytopenia (1.1%).

Quizartinib and AC886 are mainly metabolised by CYP3A, so strong inhibitors and inducers of this enzyme change exposure, and other QT-prolonging medicines add to its effect on the QT interval.

• Strong CYP3A/P-gp inhibitors (itraconazole, posaconazole, voriconazole, clarithromycin, nefazodone, telithromycin and some antiretrovirals): ketoconazole raised quizartinib exposure (AUC) 1.94-fold after a single dose and an estimated 1.96-fold at steady state, which may increase toxicity. If the combination cannot be avoided, reduce the quizartinib dose (see Administration and Dosage). Among HIV medicines, ritonavir may increase side effects, whereas efavirenz or etravirine may reduce effectiveness.
• Moderate CYP3A inhibitors: fluconazole changed exposure by about 1.2-fold at most, which was not clinically relevant; no dose modification.
• Strong or moderate CYP3A inducers: efavirenz lowered quizartinib exposure (AUC) about 9.7-fold and that of AC886 about 26-fold, which may reduce efficacy. Avoid the combination. Strong inducers include apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampicin and St John’s wort; moderate inducers include efavirenz, bosentan, etravirine, phenobarbital and primidone.
• Weak CYP3A inducers: rufinamide caused no clinically meaningful change; no dose modification.
• QT-prolonging medicines: co-administration may further increase QT prolongation. Examples named in the SmPC are antifungal azoles, ondansetron, granisetron, azithromycin, pentamidine, doxycycline, moxifloxacin, atovaquone, prochlorperazine and tacrolimus. Use with caution and with more frequent ECGs.
• Gastric acid-reducing agents: lansoprazole had no clinically relevant effect on absorption; no dose modification.
• P-gp substrates: quizartinib is a weak P-gp inhibitor; dabigatran exposure rose by about 1.1-fold, and no dose modification is recommended.
• BCRP substrates: quizartinib inhibits BCRP in vitro and the clinical relevance is unknown. Use caution and consider a lower dose of the BCRP substrate.
• Food: quizartinib may be taken with or without food.

Treatment must be started by a physician experienced in the use of anti-cancer therapies. Before the first dose, FLT3-ITD-positive AML must be confirmed with a CE-marked in vitro diagnostic test (or, if none is available, another validated test), an ECG must be performed and any electrolyte abnormality corrected. The tablets are taken by mouth at about the same time each day, with or without food.

Recommended Dose

• Induction: 35.4 mg (2 × 17.7 mg) once daily for two weeks in each induction cycle, together with standard chemotherapy. Start on day 8 with a 7 + 3 regimen, or on day 6 when a 5 + 2 regimen is used as the second induction cycle. Up to 2 induction cycles.
• Consolidation: for patients in complete remission (CR) or complete remission with incomplete haematologic recovery (CRi), 35.4 mg once daily for two weeks in each consolidation cycle, starting on day 6. Up to 4 consolidation cycles.
• Maintenance: single-agent quizartinib starting at 26.5 mg once daily for two weeks if QTcF is ≤ 450 ms. After two weeks, if QTcF is still ≤ 450 ms, the dose is increased to 53 mg (2 × 26.5 mg) once daily. Dosing is continuous, with no break between 28-day cycles, for up to 36 cycles.
• Stem cell transplantation: stop quizartinib 7 days before the start of the conditioning regimen. It may be resumed after the transplant, at the doses above, based on white blood cell count and at the treating physician’s discretion, in patients with sufficient haematologic recovery and graft-versus-host disease of grade 2 or lower that has not needed new systemic GVHD therapy within 21 days.

Dose Adjustments

Grades follow NCI CTCAE version 4.03.

• QTcF 450–480 ms (grade 1): continue the dose.
• QTcF 481–500 ms (grade 2): reduce the dose without interruption. Resume the previous dose in the next cycle if QTcF has fallen below 450 ms, and monitor closely for QT prolongation during the first cycle at the increased dose.
• QTcF 501 ms or more (grade 3): interrupt, then resume at a reduced dose when QTcF returns to below 450 ms. Do not escalate to 53 mg in maintenance if a QTcF above 500 ms was seen during induction or consolidation and is suspected to be related to quizartinib; stay at 26.5 mg once daily. If a QTcF above 500 ms recurs despite dose reduction and correction of other risk factors (electrolyte abnormalities, other QT-prolonging medicines), stop permanently.
• Torsade de pointes, polymorphic ventricular tachycardia or signs of life-threatening arrhythmia (grade 4): stop permanently.
• Grade 3 or 4 non-haematologic reactions: interrupt. Resume at the previous dose if the reaction improves to grade 1 or lower, or at a reduced dose if it improves to below grade 3. Stop permanently if it persists beyond 28 days and is suspected to be related to quizartinib.
• Persistent grade 4 neutropenia or thrombocytopenia without active bone marrow disease: reduce the dose.

Dose Levels by Phase

The reduced dose depends on the phase of treatment and on whether the reduction is for an adverse reaction, for a strong CYP3A inhibitor, or for both.

• Induction or consolidation (full dose 35.4 mg): 26.5 mg for an adverse reaction; 17.7 mg with a strong CYP3A inhibitor; interrupt if both apply.
• Maintenance, first two weeks (full dose 26.5 mg): interrupt for an adverse reaction; 17.7 mg with a strong CYP3A inhibitor; interrupt if both apply.
• Maintenance after two weeks (full dose 53 mg): 35.4 mg for an adverse reaction; 26.5 mg with a strong CYP3A inhibitor; 17.7 mg if both apply.

Special Populations

• Elderly: no dose adjustment (see Special Instructions for infections in patients over 65).
• Hepatic impairment: no adjustment in mild or moderate impairment; not recommended in severe impairment (Child-Pugh class C), because safety and efficacy have not been established.
• Renal impairment: no adjustment in mild or moderate impairment; not recommended in severe impairment (creatinine clearance below 30 mL/min by Cockcroft-Gault), because safety and efficacy have not been established.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed or Vomited Dose

If a dose is missed or not taken at the usual time, take it as soon as possible on the same day and return to the usual schedule the next day. Never take two doses on the same day. If vomiting follows a dose, do not take an extra dose that day; take the next dose the following day at the usual time.

FLT3-ITD Confirmation

Quizartinib may be used only in AML confirmed as FLT3-ITD positive, using a CE-marked in vitro diagnostic test with the corresponding intended purpose or, if none is available, another validated test.

QT Interval Prolongation and ECG Monitoring

• Quizartinib prolongs the QT interval, which may increase the risk of ventricular arrhythmias or torsade de pointes. It must not be used in congenital long QT syndrome; patients with this syndrome or a history of torsade de pointes were excluded from the development programme.
• Do not start treatment if the QTcF interval is above 450 ms. Before treatment, perform an ECG and correct electrolyte abnormalities.
• Induction and consolidation: ECG before starting and then once weekly during quizartinib treatment, or more often if clinically indicated.
• Maintenance: ECG before starting and then once weekly for the first month after dose initiation and after each dose escalation, and thereafter as clinically indicated. Do not escalate the starting dose if QTcF is above 450 ms.
• Monitor and correct hypokalaemia and hypomagnesaemia before and during treatment, and check electrolytes and ECGs more often in patients with diarrhoea or vomiting.
• Use with caution, and with more frequent ECGs, in patients at significant risk of QT prolongation: those with uncontrolled or significant cardiovascular disease (for example second- or third-degree heart block without a pacemaker, myocardial infarction within 6 months, uncontrolled angina pectoris, uncontrolled hypertension, congestive heart failure, or a history of clinically relevant ventricular arrhythmias or torsade de pointes) and those taking QT-prolonging medicines.
• Stop permanently in QT prolongation with signs or symptoms of life-threatening arrhythmia.

Strong CYP3A Inhibitors

Strong CYP3A inhibitors raise quizartinib exposure, so the dose must be reduced when they are used together (see Administration and Dosage).

Infections in Elderly Patients

Fatal infections occurred more often with quizartinib in patients older than 65 years than in younger patients (13% versus 5.7%), especially early in treatment. Patients over 65 should be closely monitored for severe infections during induction.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: women of childbearing potential should have a pregnancy test within 7 days before starting and use effective contraception during treatment and for at least 7 months after the last dose. Male patients with female partners of childbearing potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: there are no data in pregnant women. Animal findings suggest quizartinib may cause embryo-foetal harm. It should not be used during pregnancy, or in women of childbearing potential not using contraception, unless the woman’s clinical condition requires treatment.
• Breastfeeding: it is unknown whether quizartinib or its active metabolites pass into human milk. Women must not breast-feed during treatment and for at least 5 weeks after the last dose.
• Fertility: there are no human data; animal findings suggest female and male fertility may be impaired.

Effect on Driving

Quizartinib has no or negligible influence on the ability to drive and use machines.

Vanflyta tablets need no special storage conditions. They are supplied in aluminium/aluminium perforated unit-dose blisters: 17.7 mg in cartons of 14 × 1 or 28 × 1 tablets, and 26.5 mg in cartons of 14 × 1, 28 × 1 or 56 × 1 tablets. Not all pack sizes may be marketed.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment must be started by a physician experienced in anti-cancer therapy, only after FLT3-ITD-positive AML has been confirmed with a CE-marked test, a baseline ECG has been done and electrolyte abnormalities have been corrected; ECG and electrolyte monitoring continue throughout treatment. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.