Effect of Gastric Acid Reducing Agents on Glasdegib:

Coadministration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUCinf but
decreased Cmax by 20%.
In Vitro Studies
Effect of Glasdegib on Cytochrome P450 (CYP) Substrates:
Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does
not induce CYP1A2, CYP2B6, and CYP3A in vitro.
Effect of Transporters on Glasdegib:
Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Effect of Glasdegib on Transporters:
Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but notorganic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, andorganic cation transporter (OCT)2 in vitro.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with glasdegib.
Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic inthe in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic or aneugenic inthe rat micronucleus assay.
Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males.
Menshould seek advice on effective fertility preservation before treatment. In repeat-dose toxicity studies in rats,findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete
loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did notrecover whereas testicular degeneration did recover. The dose at which testicular effects were observed in malerats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times
(based on AUC) those associated with the observed human exposure at the 100 mg once daily dose.
14 CLINICAL STUDIES
The efficacy of DAURISMO in combination with low-dose cytarabine was eva luated in a multicenter, openlabel,randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 yearsor older with newly-diagnosed AML who met at least one of the following criteria: a) age > 75 years, b) severecardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, ord) baseline serum creatinine >1.3 mg/dL. Patients were randomized 2:1 to receive DAURISMO at a 100 mgdaily dose with low-dose cytarabine 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 unacceptabletoxicity. Patients were stratified by cytogenetic risk (good/intermediate or poor).
The baseline demographic and disease characteristics are shown in Table 5. The two treatment arms weregenerally balanced with respect to the baseline demographics and disease characteristics (see Table 5).
Table 5. Baseline Demographic and Disease Characteristics in Patients wit