Evaluation of the Relationship of Glasdegib Exposure and Safety End Points in Patients With Refractory Solid Tumors and Hematologic Malignancies

Abstract

Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposureefficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Estimated pharmacokinetic parameters were used to derive glasdegib exposure metrics. Demographic characteristics, disease factors, and other variables of interest as potential moderators of safety signals were evaluated. Clinical trial data from patients who received single-agent glasdegib (N = 70; 5-640 mg once daily); or glasdegib (N = 202, 100-200 mg once daily) with low-dose cytarabine, decitabine, or daunorubicin and cytarabine were analyzed. Glasdegib exposure was statistically significantly associated with the cluster term safety end points dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged. The impact of age on muscle spasms and baseline body weight and creatinine clearance on renal toxicity helped explain the AE grade distribution. At the 100 mg once daily clinical dose, the predicted probabilities of the highest AE grade were 11.3%, 6.7%, 7.7%, and 2.5% for dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged, respectively. Overall, the predicted probability of developing an AE of any severity for these safety end points was low. Therefore, no starting dose adjustments are recommended for glasdegib based on the observed safety profile.

Update on glasdegib in acute myeloid leukemia – broadening horizons of Hedgehog pathway inhibitors

“…The most commonly observed adverse effects of glasdegib in clinical trials were hematologic disorders (anaemia, febrile neutropenia, thrombocythemia), nausea, decreased appetite, fatigue, muscle spasms, diarrhea and pneumonia (47,50,51). Most of these AEs appeared to be exposure-dependent (93). In the randomized arm of the BRIGHT AML 1003 study (26), grade 3-4 AEs occurred in 64.3 and 56.1 % of patients in the glasdegib + LDAC group and in the LDAC group, respectively.…”

Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

“…An exposure-toxicity analysis was conducted for creatine kinase increase, but no relationship was observed [ 105 , 106 ]. For glasdegib, no exposure-response relationship was seen for OS and radiological response, but exposure was significantly associated with dysgeusia, muscle spasms, renal toxicity and QTc-time prolongation ( n = 75–272) [ 107 – 109 ] Therapeutic drug monitoring in hedgehog pathway inhibitors could therefore primarily be of valuable in preventing excessive toxicity in patients using glasdegib [ 108 ].…”