In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
Late in 2018, the Hedgehog pathway inhibitor glasdegib was approved for use in combination with low-dose cytarabine in the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 75 years of age and older or who have comorbidities that preclude intensive induction chemotherapy.1,2 Glasdegib has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment.
Supporting Efficacy Data
Approval was based on overall survival outcomes in the open-label BRIGHT AML 1003 trial (ClinicalTrials.gov identifier NCT01546038). This study included 115 patients with newly diagnosed AML who met at least one of the following criteria: age 75 years or older (61% of glasdegib group vs 61% of control group), severe cardiac disease (66% vs 53%), baseline Eastern Cooperative Oncology Group performance status of 2 (53% vs 47%), or baseline serum creatinine of at least 1.3 mg/dL (19% vs 13%).2 Patients were randomly assigned 2:1 to receive oral glasdegib at 100 mg daily with low-dose cytarabine at 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (n = 77) or low-dose cytarabine alone (n = 38) in 28-day cycles until disease progression or unacceptable toxicity.
With a median follow-up of 20 months, median overall survival was 8.3 months with glasdegib plus low-dose cytarabine vs 4.3 months with low-dose cytarabine alone (hazard ratio = 0.46, P = .0002). Complete response rates were 18.2 vs 2.6%.
How It Works
Glasdegib is an inhibitor of the Hedgehog pathway. The agent binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine inhibited increases in tumor size and reduced the percentage of CD45-positive/CD33-positive blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone.
How It Is Used
The recommended dose of glasdegib is 100 mg orally once daily on days 1 to 28 in combination with cytarabine at 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treatment should continue for a minimum of six cycles to allow time for clinical response.
Complete blood cell counts, electrolytes, and renal and hepatic function should be monitored prior to the initiation of treatment and at least once weekly for the first month. Electrolytes and renal function should be monitored once monthly for the duration of therapy. Serum creatine kinase levels should be obtained prior to initiating treatment and as indicated clinically thereafter (eg, if muscle symptoms are reported). Electrocardiograms (ECGs) should be monitored prior to the initiation of treatment, approximately 1 week after initiation, and then once monthly for the next 2 months to assess for QTc prolongation. ECGs should be repeated if results are abnormal. Certain patients may require more frequent and ongoing ECG monitoring.
Product labeling provides instructions on management and glasdegib dose modification for QTc interval prolongation on at least two separate ECGs; hematologic toxicity; and grade 3 or 4 nonhematologic toxicity. Glasdegib should be permanently discontinued for QTc interval prolongation with life-threatening arrhythmia; platelet count less than 10 × 109/L for more than 42 days in the absence of disease (both glasdegib and low-dose cytarabine discontinued); neutrophil count less than 0.5 × 109/L for more than 42 days in the absence of disease (both agents discontinued); grade 3 nonhematologic adverse events that recur after dose interruption and modification (both agents discontinued unless adverse event is attributed to glasdegib); and any grade 4 nonhematologic adverse event (both agents discontinued).
For concomitant use of glasdegib with strong CYP3A inhibitors, alternative therapies that are not strong CYP3A inhibitors should be considered, or patients should be monitored for increased risk of adverse reactions, including QTc interval prolongation. Concomitant use of glasdegib with strong CYP3A4 inducers should be avoided. Concomitant use with QTc-prolonging drugs should be avoided; if co-administration cannot be avoided, patients must be monitored for increased risk of QTc interval prolongation.
The most common adverse events of any grade with glasdegib plus low-dose cytarabine were anemia (43% vs 42% with low-dose cytarabine alone), fatigue (36% vs 32%), hemorrhage (36% vs 42%), febrile neutropenia (31% vs 22%), musculoskeletal pain (30% vs 17%), edema (30% vs 20%), thrombocytopenia (30% vs 27%), nausea (29% vs 12%), dyspnea (23% vs 24%), decreased appetite (21% vs 7%), dysgeusia (21% vs 2%), mucositis (21% vs 12%), constipation (20% vs 12%), and rash (20% vs 7%). The most common grade ≥ 3 adverse events included anemia (41% vs 37%), febrile neutropenia (31% vs 22%), thrombocytopenia (30% vs 24%), pneumonia (15% vs 22%), and fatigue (14% vs 7%).
Serious adverse events were reported in 79% of the glasdegib group, with the most common being febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). Adverse events led to dose reduction in 26% of the group, with the most common causes being muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and QT prolongation (2%). Adverse events led to permanent treatment discontinuation in 36%.
Glasdegib has a boxed warning for embryofetal toxicity. Women of reproductive potential should undergo pregnancy testing prior to initiation of treatment and should be advised to use effective contraception during treatment and for at least 30 days after the last dose. Men should be advised of the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment and for at least 30 days after the last dose. Glasdegib has warnings/precautions for blood donation and QTc prolongation. Patients should be advised not to donate blood or blood products during treatment and for at least 30 days after the last dose. Women should not breastfeed during treatment with glasdegib.
1. U.S. Food and Drug Administration: FDA approves glasdegib for AML in adults age 75 or older or who have comorbidities. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626494.htm. Accessed November 21, 2019.
2. Daurismo (glasdegib) tablets prescribing information, Pfizer Labs, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf. Accessed November 21, 2019.