FDA Approves DAURISMO with Cytarabine for AML

The U.S. Food and Drug Administration (FDA) approved DAURISMO (glasdegib), in combination with low-dose cytarabine, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adult patients who are ≥ 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. The approved recommended dosage of DAURISMO is 100 mg orally once daily with or without food on days 1 to 28 in combination with cytarabine 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, treat for a minimum of 6 cycles to allow time for clinical response.

Assess complete blood counts, electrolytes, renal function, hepatic function, and serum creatine kinase levels prior to initiating DAURISMO and thereafter as recommended in the full prescribing information linked below. Monitor electrocardiograms and electrolytes. Additional information regarding recommended dosage modifications or discontinuation for adverse reactions including QT-prolongation can be found in the full prescribing information linked below. DAURISMO has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment.

DAURISMO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Recommendations for contraception for women of reproductive potential and male patients with female partners can be found in the full prescribing information linked below. Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose. Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction.

General PK: DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the approved recommended dosage) result in a dose proportional increase in glasdegib Cmax and AUCtau. Steady-state plasma levels are reached by 8 days of daily dosing. The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing. At DAURISMO 100 mg once daily, the geometric mean (%CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUCtau was 17210 ng*hr/mL (54%) in patients with cancer.

Absorption: The mean absolute bioavailability of DAURISMO is 77%. Following 100 mg once daily dosing, glasdegib median Tmax at steady-state ranged from 1.3 hours to 1.8 hours.

Distribution: Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.

Elimination: The mean (± SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following approved recommended dosage in patients with hematologic malignancies.

Metabolism: Primarily metabolized by CYP3A4, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma.

Excretion: Forty-nine percent (49%; 17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) was eliminated in the feces.

Cardiac Electrophysiology: Glasdegib is associated with concentration-dependent QTc prolongation. In healthy subjects, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms) at plasma concentrations achieved with the recommended dose, and 13 ms (90% CI: 11, 16 ms) at a two-fold therapeutic plasma concentration.

Consider alternative therapies that are not strong CYP3A inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation. Avoid co-administration of strong CYP3A4 inducers. Avoid co-administration of QTc prolonging drugs with DAURISMO or replace with alternative therapies. If co-administration of a QTc prolonging drug is unavoidable, monitor for increased risk of QTc interval prolongation.

No dose adjustment is recommended for age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1-1.5 x ULN and any AST) or mild to moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min). The effect of moderate (total bilirubin 1.5-3 x ULN and any AST) and severe (total bilirubin > 3 x ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15-29 mL/min) on glasdegib pharmacokinetics is unknown. 

Efficacy of DAURISMO in combination with low-dose cytarabine was demonstrated in a multicenter, open-label, randomized study that enrolled adult patients age 55 years or older with newly-diagnosed AML. Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause. Additional information regarding this efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence ≥ 20%) are anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

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