Quizartinib

Quizartinib, sold under the brand name Vanflyta, is an anti-cancer medication used for the treatment of acute myeloid leukemia.^[2]

Quizartinib

Names
Preferred IUPAC name N-(5-tert-Butyl-1,2-oxazol-3-yl)-N′-(4-{7-[2-(morpholin-4-yl)ethoxy]imidazo[2,1-b][1,3]benzothiazol-2-yl}phenyl)urea
Other names AC220 AC010220 Vanflyta
Identifiers
CAS Number	950769-58-1 Y[PubChem] 1132827-21-4
3D model (JSmol)	Interactive image
ChEBI	CHEBI:90217 Y
ChEMBL	ChEMBL576982 Y ChEMBL2105709
ChemSpider	24640357 Y 25069710
DrugBank	DB12874 DBSALT003051
IUPHAR/BPS	5658
KEGG	D09955 D09956
PubChem CID	24889392
UNII	7LA4O6Q0D3 Y WK7Q6ZIZ10
CompTox Dashboard (EPA)	DTXSID70241746
InChI InChI=1S/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36) N Key: CVWXJKQAOSCOAB-UHFFFAOYSA-N N InChI=1/C29H32N6O4S/c1-29(2,3)25-17-26(33-39-25)32-27(36)30-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)40-28(35)31-22)38-15-12-34-10-13-37-14-11-34/h4-9,16-18H,10-15H2,1-3H3,(H2,30,32,33,36) Key: CVWXJKQAOSCOAB-UHFFFAOYAF
SMILES CC(C)(C)c1cc(no1)NC(=O)Nc2ccc(cc2)c3cn4c5ccc(cc5sc4n3)OCCN6CCOCC6
Properties
Chemical formula	C29H32N6O4S
Molar mass	560.67 g·mol−1
Pharmacology
ATC code	L01EX11 (WHO)
Legal status	US: ℞-only[1][2] EU: Rx-only[3][4]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

Quizartinib

Clinical data
License data	US DailyMed: Quizartinib
Drug class	Receptor tyrosine kinase inhibitor
Legal status
Legal status	US: WARNING[5]
Identifiers
PDB ligand	P30 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID70241746

It is a small molecule receptor tyrosine kinase inhibitor. Its molecular target is FLT3, also known as CD135 which is a proto-oncogene.^[6] FLT3 mutations are among the most common mutations in acute myeloid leukemia due to internal tandem duplication of FLT3, and the presence of this mutation is a marker of adverse outcome.^[7]

The most common side effects of include low white blood cell counts with or without fever, reduced levels of electrolytes (potassium, magnesium or calcium) in blood, increased levels of liver or muscles enzymes, diarrhea, ulcers or redness inside the mouth (mucositis), nausea, abdominal pain, sepsis (serious infection throughout the body and organs), headache, vomiting, and upper respiratory tract infection.^[8]

It was approved for medical use in Japan in October 2019,^[9] in the United States in July 2023,^[2] and the European Union in November 2023.^[3]

Medical uses

Quizartinib is indicated, in combination with standard cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of newly diagnosed acute myeloid leukemia with FLT3 internal tandem duplication (ITD)-positive.^[2][3]

Adverse effects

The US Food and Drug Administration (FDA) label includes a boxed warning noting QT prolongation, torsades de pointes, and cardiac arrest.^[2][8]

Quizartinib may cause harm to an unborn baby (embryo-fetal toxicity).^[8]

Mechanism of action

Quizartinib selectively inhibits class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3 (FLT3/STK1), colony-stimulating factor 1 receptor (CSF1R/FMS), stem cell factor receptor (SCFR/KIT), and platelet derived growth factor receptors (PDGFRs).^[10]

Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.^[10]

History

Efficacy of quizartinib with chemotherapy was evaluated in QuANTUM-First (NCT02668653), a randomized, double-blind, placebo-controlled trial of 539 participants with newly diagnosed FLT3 internal tandem duplication positive acute myeloid leukemia.^[2] FLT3 internal tandem duplication status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay.^[2] Participants were randomized (1:1) to receive quizartinib (n=268) or placebo (n=271) with induction and consolidation therapy and as maintenance monotherapy according to the initial assignment.^[2] There was no re-randomization at the initiation of post-consolidation therapy.^[2] Participants who proceeded to hematopoietic stem cell transplantation initiated maintenance therapy after hematopoietic stem cell transplantation recovery.^[2]

The main efficacy outcome measure was overall survival, measured from randomization date until death by any cause.^[2] The primary analysis was conducted after a minimum follow-up of 24 months after the last patient was randomized.^[2] The trial demonstrated a statistically significant improvement in overall survival for the quizartinib arm [hazard ratio (HR) 0.78; 95% CI: 0.62, 0.98; 2‑sided p=0.0324].^[2] The CR rate in the quizartinib arm was 55% (95% CI: 48.7, 60.9) with a median duration of 38.6 months (95% CI: 21.9, NE), and the CR rate in those receiving placebo was 55% (95% CI: 49.2, 61.4) with a median duration of 12.4 months (95% CI: 8.8, 22.7).^[2]

The FDA granted the application for quizartinib priority review, fast track, and orphan drug designations.^[2]

Clinical trials

It reported good results in 2012, from a phase II clinical trial for refractory acute myeloid leukemia - in participants who went on to have a stem cell transplant.^{[11][unreliable medical source?]}

As of July 2023^[update], it has completed seventeen clinical trials, and another eleven are active.^[12]

Society and culture

Legal status

The application for quizartinib was denied in the European Union in 2019.^[13]

In September 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vanflyta, intended for the treatment of acute myeloid leukaemia (AML) that is FLT3-ITD positive.^[3] The applicant for this medicinal product is Daiichi Sankyo Europe GmbH.^[3]

Quizartinib was approved for medical use in Japan in October 2019,^[9] in the United States in July 2023,^[2] and the European Union in November 2023.^[3][4]

Brand names

Quizartinib is the international nonproprietary name.^[14]

Quizartinib is sold under the brand name Vanflyta.^[1][3]

References

1. "Vanflyta- quizartinib tablet, film coated". DailyMed. 26 July 2023. Archived from the original on 7 August 2023. Retrieved 6 August 2023.
2. "FDA approves quizartinib for newly diagnosed acute myeloid leukemia". U.S. Food and Drug Administration (FDA). 20 July 2023. Archived from the original on 21 July 2023. Retrieved 21 July 2023. This article incorporates text from this source, which is in the public domain.
3. "Vanflyta EPAR". European Medicines Agency. 21 November 2023. Archived from the original on 22 November 2023. Retrieved 22 November 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
4. "Vanflyta Product information". Union Register of medicinal products. 7 November 2023. Archived from the original on 13 November 2023. Retrieved 13 November 2023.
5. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
6. Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, et al. (December 2009). "Identification of N-(5-tert-Butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor". Journal of Medicinal Chemistry. 52 (23): 7808–7816. doi:10.1021/jm9007533. PMID 19754199.
7. Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L, et al. (July 2005). "Internal tandem duplications of the FLT3 gene are present in leukemia stem cells". Blood. 106 (2): 673–80. doi:10.1182/blood-2004-05-1902. PMC 1895185. PMID 15797998.
8. "Drug Trials Snapshots: Vanflyta". U.S. Food and Drug Administration (FDA). 20 July 2023. Retrieved 18 April 2024. This article incorporates text from this source, which is in the public domain.
9. "Daiichi Sankyo Launches FLT3 Inhibitor Vanflyta in Japan for the Treatment of Patients with Relapsed/Refractory FLT3-ITD AML" (Press release). Archived from the original on 10 August 2023. Retrieved 16 February 2021.
10. Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Döhner H, Döhner K, Schittenhelm MM (March 2013). "Quizartinib (AC220) is a potent second generation class III tyrosine kinase inhibitor that displays a distinct inhibition profile against mutant-FLT3, -PDGFRA and -KIT isoforms". Molecular Cancer. 12: 19. doi:10.1186/1476-4598-12-19. PMC 3637582. PMID 23497317.
11. "Drug Tames Refractory AML. ASH Dec 2012". 9 December 2012. Archived from the original on 8 August 2014. Retrieved 16 December 2012.
12. "Quizartinib studies". Archived from the original on 21 February 2017. Retrieved 20 February 2017.
13. "Vanflyta". European Medicines Agency. 6 January 2020. Archived from the original on 27 January 2023. Retrieved 6 August 2023.
14. World Health Organization (2011). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 66". WHO Drug Information. 25 (3). hdl:10665/74683.

Further reading

• Erba HP, Montesinos P, Kim HJ, Patkowska E, Vrhovac R, Žák P, et al. (May 2023). "Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial". Lancet. 401 (10388): 1571–1583. doi:10.1016/S0140-6736(23)00464-6. PMID 37116523. S2CID 258314572.

External links

• Clinical trial number NCT02668653 for "Quizartinib With Standard of Care Chemotherapy and as Continuation Therapy in Patients With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (AML) (QuANTUM-First)" at ClinicalTrials.gov