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Glasdegib (Daurismo™)

Lovell, Alex, PharmD; Mann, Janelle E., PharmD, BCOP

doi: 10.1097/01.COT.0000557871.59318.1a
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What is glasdegib?

Glasdegib is a hedgehog pathway inhibitor approved by the FDA in 2018. Hedgehog inhibitors have been used in basal cell carcinoma, but glasdegib is the first hedgehog inhibitor to be approved in acute myeloid leukemia (AML).

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How does glasdegib work?

The hedgehog pathway is implicated in AML. Abnormal activation of the hedgehog pathway is thought to contribute to the development of malignant stem cells and resistance to chemotherapy. Glasdegib binds to a transmembrane protein called Smoothened, inhibiting hedgehog signaling (Cell Commun Signal 2017;15(1):8).

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What is this approved for?

Glasdegib is FDA-approved for use in combination with low-dose cytarabine for the treatment of newly diagnosed AML in patients ≥ 75 years old or who have comorbidities that preclude use of intensive induction therapy.

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What is the basis for this approval?

Glasdegib was approved in November 2018 based on the results of the BRIGHT trial, a phase Ib/II, open-label, multi-center, randomized study that included 115 patients. Patients must have had factors that precluded them from receiving intensive induction therapy such as age ≥ 75 years, severe cardiac disease, ECOG of 2, or baseline serum creatinine > 1.3 mg/dL. Patients received glasdegib 100 mg PO once daily on days 1-28 in combination with low-dose cytarabine 20 mg subcutaneously twice daily on days 1-10 of a 28-day cycle or cytarabine alone. Sixty-one percent of the population was greater than 75 years old. After a mean follow-up of 20 months, the median overall survival in the glasdegib + cytarabine group was 8.3 months compared to 4.3 months in the cytarabine alone group. The complete response rates were 18.2 percent in the glasdegib + cytarabine group compared to 2.6 percent in the cytarabine alone group.

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How do you administer this drug?

Glasdegib should be initiated at 100 mg once daily without regards to meals and should be given in combination with low-dose cytarabine 20 mg subcutaneously twice daily on days 1-10 of a 28-day cycle. Therapy should continue until disease progression or unacceptable toxicity. Patients tolerating treatment should continue for a minimum of 6 cycles to allow time for clinical response.

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Are there any premedications needed for glasdegib?

None required.

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What are the common side effects associated with glasdegib (> or = 10%)?

In the BRIGHT trial, the most common toxicities of any grade included anemia, hemorrhage, febrile neutropenia, thrombocytopenia, fatigue, edema, musculoskeletal pain, and nausea. Grade 3 or greater adverse events were less common, but included anemia, febrile neutropenia, thrombocytopenia, fatigue, and infection, including pneumonia.

Dose reductions were associated with adverse reactions in 26 percent of patients, mostly due to muscle spasms, fatigue, and febrile neutropenia.

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What are the uncommon side effects associated with glasdegib (less than 10%?)

Less common toxicities include dental disorders, alopecia, and prolonged QTc interval.

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Are there any important drug interactions I should be aware of?

Glasdegib is metabolized primarily by CYP3A4 with minor contributions by CYP2C8 and UGT1A9. Co-administration with strong CYP3A4 inhibitors could increase glasdegib plasma concentrations and close monitoring is necessary to assess risk of toxicity. Co-administration with strong CYP3A4 inducers may decrease glasdegib plasma levels and should be avoided. Avoid co-administration with other drugs that prolong the QTc interval or monitor closely if co-administration is unavoidable.

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How do I adjust the dose in the setting of renal or hepatic insufficiency?

Glasdegib has not been studied in patients with severe renal impairment or moderate-to-severe hepatic impairment.

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Practical tips

Glasdegib is only approved in combination with subcutaneous cytarabine. Glasdegib schedule of administration in combination with subcutaneous drug administration BID for 10 days should be reviewed with the patient and assess ability to maintain this schedule.

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What should my patients know about glasdegib?

  • Patients should report any bleeding or heart palpitations while taking glasdegib.
  • Glasdegib should not be used in pregnancy. Men and women on glasdegib should use effective birth control during treatment and for at least 30 days after the last dose.
  • Responses to therapy may take up to 6 cycles.
  • Patients should be aware that drug interactions are common, and they should report any new medications to the treatment team.
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What useful links are available regarding glasdegib?

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Any ongoing clinical trials related to glasdegib?

A randomized phase III study, BRIGHT AML1019, is currently enrolling, which is investigating the use of glasdegib in combination with intensive chemotherapy or azacitadine for untreated AML. More information is available at www.clinicaltrials.gov.

ALEX LOVELL, PHARMD, is PGY2 Oncology Resident at Barnes-Jewish Hospital, St. Louis, Mo. JANELLE E. MANN, PHARMD, BCOP, is an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., and serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.

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