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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

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November 21, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210656s000lbl.pdf

On November 21, 2018, the Food and Drug Administration approved glasdegib (DAURISMO, Pfizer Labs) in combination with low-dose cytarabine (LDAC), for newly-diagnosed acute myeloid leukemia (AML) in patients who are 75 years old or older or who have comorbidities that preclude intensive induction chemotherapy.

Approval was based on a multicenter, open-label, randomized study (BRIGHT AML 1003, NCT01546038) that included 115 patients with newly-diagnosed AML who met at least one of the following criteria: a) age 75 years or older, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group performance status of 2, or d) baseline serum creatinine >1.3 mg/dL. Patients were randomized 2:1 to receive glasdegib, 100 mg daily, with LDAC 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or LDAC alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity.

Efficacy was established based on an improvement in overall survival (date of randomization to death from any cause). With a median follow-up of 20 months, median survival was 8.3 months (95% CI: 4.4, 12.2) for the glasdegib + LDAC arm and 4.3 months (95% CI: 1.9, 5.7) for the LDAC alone arm and HR of 0.46 (95% CI: 0.30, 0.71; p=0.0002).

The most common adverse reactions occurring in ≥ 20% of patients were anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

The recommended glasdegib dose is 100 mg orally, once daily. DAURISMO has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment.

View full prescribing information for DAURISMO.

FDA granted this application priority review. FDA expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Application to Practice

Glasdegib in Combination with Low-Dose Cytarabine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Patients over 74 Years of Age with Comorbidities That Preclude Intensive Chemotherapy

Authors:
Sarah Maryon Hayes, PharmD BCOP
Inpatient Hematology/Oncology Pharmacist
North Memorial Medical Center
Robbinsdale, MN

Erin Kelley, PharmD BCOP
Hematology/Oncology Clinical Pharmacy Specialist
North Memorial Health Cancer Center
Robbinsdale, MN

What is the potential role for glasdegib with low-dose cytarabine (LDAC) in the management of newly diagnosed acute myeloid leukemia (AML)?

  • Although age is not a sole determinant of treatment decisions in AML, older age is independently associated with poorer outcomes.1 Intensive treatment with chemotherapy is not an option for many older patients with comorbidities. The National Comprehensive Cancer Network (NCCN) guidelines suggest that patients with severe cardiac disease, age older than 74 years, serum creatinine >1.3 mg/dL, or Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher may fall into this category; glasdegib (with LDAC) is listed as an option for induction therapy in these patients as a category 2A recommendation.2
  • Glasdegib is a Hedgehog signaling pathway (HhP) inhibitor. Hedgehog signaling is involved in transcription factor expression in cell growth; aberrant activation contributes to the initiation and development of malignant blasts. Other U.S. Food and Drug Administration (FDA)–approved HhP inhibitors include vismodegib (Erivedge) and sonidegib (Odomzo), both used in the treatment of basal cell carcinoma.
  • The BRIGHT AML 1003 Trial (NCT01546038) was an international study of 132 patients randomized 2:1 to glasdegib plus LDAC (glasdegib 100 mg orally once daily plus LDAC 20 mg subcutaneously every 12 hours for 10 days of each 28-day cycle, n = 88) or LDAC alone (n = 44).3,4 Median overall survival (mOS) was 8.3 months (95% confidence interval [CI]: 4.4–12.2) for glasdegib plus LDAC compared with 4.3 months (95% CI: 1.9–5.7) for LDAC alone. Seventeen investigator-reported complete responses (CRs) occurred in the glasdegib plus LDAC group, compared with one CR in the LDAC group. When stratified by cytogenetic risk, the mOS was 12.2 versus 6 months (hazard ratio [HR] 0.46, p = .0035) for good and intermediate-risk patients, and 4.4 versus 2.3 months (HR 0.575, p = .0422) for poor-risk patients in favor of the glasdegib plus LDAC group.
  • The median duration of treatment with glasdegib and LDAC was 83 days (range 3–972 days), compared to a median of 47 days with LDAC alone (range 6–239 days). Glasdegib can be continued until an unacceptable toxicity level is reached or disease control is lost.4
  • Glasdegib plus LDAC is among numerous options for AML treatment without actionable mutations in patients unable to receive intensive chemotherapy, including azacitidine, decitabine, or LDAC (with or without venetoclax), and single-agent gemtuzumab ozogamicin. Low-intensity treatment with azacitidine or decitabine is currently the preferred option for patients who are not candidates for intensive induction therapy per the NCCN guidelines.2

What role can the pharmacist play in the management of patients on glasdegib?

  • Glasdegib is dosed at 100 mg by mouth once daily on days 1–28 of a 28-day cycle. LDAC is given 20 mg subcutaneously every 12 hours on days 1–10 of a 28-day cycle. Patients can take glasdegib with or without food.4
  • The most common adverse events (with an incidence of greater than 20%) included cytopenias, nausea, mucositis, taste disturbances, loss of appetite, muscle cramps, and edema. Specifically, HhP-associated adverse events were altered taste sensation (24%), muscle spasms (20%), and alopecia (11%).4
  • Four percent of patients in clinical trials demonstrated a QTc interval increase >60 msec from baseline. Glasdegib therapy for QTc interval prolongation above 500 msec should be interrupted; product labeling provides guidance on how to potentially restart glasdegib at a reduced dose if the QTc interval improves.4
  • Glasdegib is metabolized primarily through cytochrome P450 (CYP3A4) and interacts with CYP3A4 inducers and inhibitors. The pharmacist should also screen for other medications or drug-drug interactions that may result in a prolonged QTc interval, including CYP3A4 inhibitors.4
  • Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals. Glasdegib is currently FDA approved for adults 75 years or older, but if it is prescribed in a younger female of childbearing age, pregnancy testing must be conducted. Females of reproductive potential and males taking glasdegib should use effective contraception during treatment and for at least 30 days following the last dose.
  • Patient assistance is available through Pfizer Oncology at https://www.pfizeroncologytogether.com/hcp/patient-financial-assistance.

Clinical Pearls

  • HhP inhibitors are notorious for causing altered or unpleasant taste sensation due to loss of differentiation of taste cells in cells that can detect salty, sweet, and bitter tastes.5 Referral to a registered dietician may be beneficial to monitor and maintain nutritional status.
  • Muscle spasms are a common side effect of HhP inhibitors due to HhP inhibition activating calcium channels on muscle cells, inducing muscle spasms.6 Calcium channel blockade with amlodipine 10 mg daily has been used to reduce muscle spasms associated with other HhP inhibitors.7 However, use caution with amlodipine, because the incidence of edema with glasdegib plus LDAC was 30% (all grades) in the BRIGHT AML 1003 trial.3
  • The prescribing of glasdegib for patients with renal or hepatic insufficiency is currently limited. Participants are currently being recruited for a study evaluating the effects of hepatic impairment on glasdegib (NCT03627754). Results are not yet published from the study of glasdegib and renal impairment (NCT03596567); glasdegib use may be limited to those patients over 75 years old with a normal serum creatinine, though 15 patients in the BRIGHT AML 1003 Trial had a baseline creatinine >1.3 mg/dL.3,8
  • Clinical trials are currently under way for glasdegib in combination with temozolomide for glioblastoma, for refractory chronic graft-versus-host disease, for myelofibrosis refractory to ruxolitinib, and in combination with azacitidine for AML and myelodysplastic syndrome (MDS).8

References
1. Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
2. National Comprehensive Cancer Network. Acute Myeloid Leukemia. Version 2.2019. Released March 9, 2019.Retrieved from https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed March 26,2019.
3. Cortes JE, Heidel FH, Heuser M, et al. A phase 2 randomized study of low dose Ara-C with or without glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2016;128:99.
4. Daurismo (glasdegib) tablets for oral use [package insert]. New York, NY: Pfizer, Inc.; 2018.
5. Yang H, Cong WN, Yoon JS, Egan JM. Vismodegib, an antagonist of hedgehog signaling, directly alters taste molecular signaling in taste buds. Cancer Med. 2015;4(2):245-252.
6. Teperino R, Amann S, Bayer M, et al. Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell. 2012;151(2):414-426.
7. Ally MS, Tang JY, Lindgren J, et al. Effect of calcium channel blockade on vismodegib-induced muscle cramps. JAMA Dermatol. 2015;151(10):1132-1134.
8. ClinicalTrials.gov. Bethesda, MD: U.S. National Library of Medicine. Available at https://www.clinicaltrials.gov/ct2/results?cond=&term=glasdegib&cntry=&state=&city=&dist=. Accessed February 19, 2019.

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