OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Glasdegib	1095173-27-5	C21-H22-N6-O

ANNOTATED BIBLIOGRAPHY

References updated: 20 January 2019

Abbreviation: AML, acute myelogenous leukemia.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of kinase inhibitors).
• DeLeve LD. Erlotinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013 before the availability of glasdegib and other hedgehog inhibitors).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/scripts/cder/daf/

  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy; mentions glasdegib- and comparator-treatment had similar rates of elevations in ALT [31% vs 28%], AST [36% vs 30%] and alkaline phosphatase [29% vs 30%], and no patient developed clinically apparent liver injury).
• Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, et al. Phase Ib study of glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res 2018; 24: 2294-303. [PubMed: 29463550]

  (Among 52 patients with AML or myelodysplastic syndromes treated with glasdegib [100 or 200 mg daily] combined with cytarabine or decitabine alone or cytarabine and daunorubicin, complete responses occurred in 16 [31%] and adverse event rates were common but considered manageable; no mention of ALT elevations or hepatotoxicity).
• Cortes JE, Douglas Smith B, Wang ES, Merchant A, Oehler VG, Arellano M, DeAngelo DJ, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol 2018; 93: 1301-10. [PMC free article: PMC6221102] [PubMed: 30074259]

  (Among 69 patients with AML or myelodysplastic syndromes treated with glasdegib orally once daily with intravenous cytarabine and daunorubicin in six 28-day cycles, 47% had a complete remission, but all had adverse events that were often severe, including febrile neutropenia [64%], anemia [41%] and ALT elevations [30%], some being above 5 times ULN [5.7%]).
• Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, Montesinos P, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 2019; 33: 379-89. [PMC free article: PMC6365492] [PubMed: 30555165]

  (Among 132 patients with AML or high-risk myelodysplastic syndromes who were treated with intravenous cytarabine with or without oral glasdegib, median overall survival was greater with the combination [8.8 vs 4.9 months] while adverse events rates were similar, serious adverse events occurring in 78% vs 79% of patients and liver test abnormalities in 11% vs 10% all of which were transient, without symptoms or jaundice and not necessitating drug discontinuation).
• Hoy SM. Glasdegib: first global approval. Drugs 2019; 79: 207-13. [PubMed: 30666593]

  (Review of the mechanism of action, history of development, pharmacology, efficacy and safety of glasdegib shortly after its initial approval as therapy of AML; mentions that liver enzyme elevations were frequent during glasdegib therapy, and they were not associated with jaundice or symptoms and did not require early drug discontinuation).