Quizartinib

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Quizartinib
Names
Trade names
  • AC220
  • AC010220
  • Vanflyta
Clinical data
Drug classReceptor tyrosine kinase inhibitor
Legal
License data
Identifiers
PDB ligand
Chemical and physical data
FormulaC29H32N6O4S
Molar mass560.67 g·mol−1
3D model (JSmol)
  • CC(C)(C)c1cc(no1)NC(=O)Nc2ccc(cc2)c3cn4c5ccc(cc5sc4n3)OCCN6CCOCC6
  • 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

Quizartinib, sold under the brand name Vanflyta, is an anti-cancer medication used to treat acute myeloid leukemia.[3] Specifically it is used with other medications to treat FLT3 internal tandem duplication (ITD)-positive disease.[3] It is taken by mouth.[3]

Common side effects of include low white blood cells, fever, low potassium, low magnesium, low calcium, increased liver or muscles enzymes, inflammation in the mouth (mucositis), nausea, abdominal pain, sepsis, headache, and upper respiratory tract infections.[3] Other side effects may include QT prolongation.[3] Use during pregnancy may harm the baby.[3] It is a receptor tyrosine kinase FLT3 inhibitor.[3]

Quizartinib was approved for medical use in Japan in 2019,[5] and the United States and Europe in 2023.[3][1] In the United States, 2 weeks worth, costs about 8,000 USD as of 2024.[6]

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.[4][1]

Side effects

The US Food and Drug Administration (FDA) label includes a boxed warning noting QT prolongation, torsades de pointes, and cardiac arrest.[4][7]

Quizartinib may cause harm to an unborn baby.[7]

Mechanism of action

Mechanism of action of type II FLT3 inhibitor[8]

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).[9]

Mutations cause constant activation of the FLT3 pathway resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis.[9] Its molecular target is FLT3, also known as CD135 which is a proto-oncogene.[10] 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 poor outcomes.[11]

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.[4] 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.[4] 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.[4] There was no re-randomization at the initiation of post-consolidation therapy.[4] Participants who proceeded to hematopoietic stem cell transplantation initiated maintenance therapy after hematopoietic stem cell transplantation recovery.[4]

The main efficacy outcome measure was overall survival, measured from randomization date until death by any cause.[4] The primary analysis was conducted after a minimum follow-up of 24 months after the last patient was randomized.[4] 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].[4] 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).[4]

The FDA granted the application for quizartinib priority review, fast track, and orphan drug designations.[4]

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.[12][unreliable medical source?]

As of July 2023, it has completed seventeen clinical trials, and another eleven are active.[13]

Society and culture

Legal status

The application for quizartinib was denied in the European Union in 2019.[14]

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.[1] The applicant for this medicinal product is Daiichi Sankyo Europe GmbH.[1]

Quizartinib was approved for medical use in Japan in October 2019,[5] in the United States in July 2023,[4] and the European Union in November 2023.[1][2]

Brand names

Quizartinib is the international nonproprietary name.[15]

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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Vanflyta EPAR". European Medicines Agency. 21 November 2023. Archived from the original on 22 November 2023. Retrieved 22 November 2023. Archived 22 November 2023 at the Wayback Machine Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  2. ↑ 2.0 2.1 "Vanflyta Product information". Union Register of medicinal products. 7 November 2023. Archived from the original on 13 November 2023. Retrieved 13 November 2023. Archived 13 November 2023 at the Wayback Machine
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 "Vanflyta- quizartinib tablet, film coated". DailyMed. 26 July 2023. Archived from the original on 7 August 2023. Retrieved 6 August 2023. Archived 7 August 2023 at the Wayback Machine
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 "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. Archived 21 July 2023 at the Wayback Machine Public Domain This article incorporates text from this source, which is in the public domain.
  5. ↑ 5.0 5.1 "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.
  6. ↑ "Vanflyta Prices, Coupons, Copay Cards & Patient Assistance". Drugs.com. Archived from the original on 19 June 2024. Retrieved 7 July 2024. Archived 19 June 2024 at the Wayback Machine
  7. ↑ 7.0 7.1 "Drug Trials Snapshots: Vanflyta". U.S. Food and Drug Administration (FDA). 20 July 2023. Archived from the original on 9 July 2024. Retrieved 18 April 2024. Archived 9 July 2024 at the Wayback Machine Public Domain This article incorporates text from this source, which is in the public domain.
  8. ↑ Biavasco, Francesca; Zeiser, Robert (September 2022). "FLT3-inhibitor therapy for prevention and treatment of relapse after allogeneic hematopoietic cell transplantation". International Journal of Hematology. 116 (3): 341–350. doi:10.1007/s12185-022-03352-6. ISSN 1865-3774.
  9. ↑ 9.0 9.1 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.
  10. ↑ Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J, Zarrinkar PP, Patel HK, Bhagwat SS (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.
  11. ↑ Levis M, Murphy KM, Pham R, Kim KT, Stine A, Li L, McNiece I, Smith BD, Small D (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.
  12. ↑ "Drug Tames Refractory AML. ASH Dec 2012". 9 December 2012. Archived from the original on 8 August 2014. Retrieved 16 December 2012. Archived 8 August 2014 at the Wayback Machine
  13. ↑ "Quizartinib studies". Archived from the original on 21 February 2017. Retrieved 20 February 2017. Archived 21 February 2017 at the Wayback Machine
  14. ↑ "Vanflyta". European Medicines Agency. 6 January 2020. Archived from the original on 27 January 2023. Retrieved 6 August 2023. Archived 27 January 2023 at the Wayback Machine
  15. ↑ World Health Organization (2011). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 66". WHO Drug Information. 25 (3). hdl:10665/74683.

External links

Identifiers:
  • 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
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