Abstract 3887: Population pharmacokinetic/pharmacodynamic evaluation of the relationship between glasdegib exposure and safety endpoints in cancer patients
Authors: Ruiz-Garcia Ana , Shaik Naveed , Jamieson Catriona , Heuser Michael , Chan Geoffrey 
Published: August 2019

Abstract
Glasdegib inhibits Hedgehog signaling through Smoothened, and is in clinical development for treating acute myeloid leukemia. This exposure-response (ER) analysis estimated the association between glasdegib exposure and incidence of the cluster terms DYSGUESIA, MUSCLE SPASMS, RENAL TOXICITY, and QT INTERVAL PROLONGED as safety endpoints (D, MS, RT, and QT) in patients receiving glasdegib as monotherapy or in combination with chemotherapy and evaluated the effect of moderators in the defined ER relationship for the different cluster terms. Ordinal logistic regression was used to model the incidence of adverse events (AEs). AEs were graded from 0-4 using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Base models were developed for each safety endpoint, selecting the most significant glasdegib exposure metric. Covariates in Table 1 were evaluated for inclusion in the model, with categorical covariates included if the incidence per category was &gt;10%. Patients received single-agent glasdegib (N=70; 5-640 mg once daily [QD]); or glasdegib (N=202, 100-200 mg QD) with low-dose cytarabine (LDAC), decitabine, or daunorubicin and cytarabine. Estimated pharmacokinetic (PK) parameters were used to derive glasdegib exposure metrics and added to the safety data analysis. Glasdegib exposure appeared to have a statistically significant association with cluster term safety endpoints D, MS, RT, and QT. The variables age on MS; and BWT and BCCL on RT help explain the AE Grade distribution. At the 100 mg QD clinical dose, the predicted probabilities of the highest AE Grade (≥3 for MS, RT and QT, and 2 for D) were 11.3%, 6.7%, 7.7%, and 2.5% for D, MS, RT, and QT respectively. Overall, the predicted probability of developing an AE of any severity for these safety endpoints was low. Therefore, no starting dose adjustments may be required based on the observed safety profile.
Table 1.Potential Covariates Evaluated:CategoryVariableTreatmentGlasdegib monotherapy, glasdegib+LDAC, glasdegib+decitabine, and glasdegib+DNR/Ara-CDemographicsSex (Male versus Female), Race, Age (years), BWT (kg)Safety laboratory information at baseline:BBIL (mg/dL), BAST (IU/L), BALT (IU/L), BALB (g/dL), BSCR (mg/dL), BCCL (mL/min), BHGB (g/dL), and BWBC (109 cells/L)Baseline Disease Status:BECOG PSAra-C=cytarabine; BALB=baseline albumin; BALT=baseline alanine transaminase; BAST=baseline aspartate transaminase; BBIL=baseline total bilirubin; BCCL=baseline creatinine clearance; BECOG=baseline Eastern Cooperative Oncology Group; BHGB=baseline hemoglobin; BSCR=baseline serum creatinine; BWBC=baseline white blood cells; BWT=baseline body weight; dL=deciliter; DNR=daunorubicin; g=gram; IU=international unit; kg=kilogram; L=liter; LDAC=low-dose cytarabine; min=minute; mg=milligram; mL=milliliter; PS=performance status.
Citation Format: Ana Ruiz-Garcia, Naveed Shaik, Catriona Jamieson, Michael Heuser, Geoffrey Chan. Population pharmacokinetic/pharmacodynamic evaluation of the relationship between glasdegib exposure and safety endpoints in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3887.