Andrew Bukowinski1, Bill Chang2, Joel M Reid3, Xiaowei Liu4, Charles G Minard5, Jane B Trepel6, Min-Jung Lee6, Elizabeth Fox7, Brenda J Weigel8. 1. Division of Pediatric Hematology Oncology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania. 2. Division of Pediatric Hematology Oncology, Oregon Health and Science University, Portland, Oregon. 3. Mayo Clinic, Rochester, Minnesota. 4. Children's Oncology Group, Operation Center, Monrovia, California. 5. Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas. 6. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 7. Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee. 8. Department of Pediatrics, University of Minnesota Masonic Cancer Center, Minneapolis, Minnesota.
Abstract
BACKGROUND: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies. METHODS: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed. RESULTS: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m2 dose level and 15 were treated in 4 mg/m2 dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses. CONCLUSIONS: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2 orally administered once weekly.
BACKGROUND: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies. METHODS: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed. RESULTS: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m2 dose level and 15 were treated in 4 mg/m2 dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses. CONCLUSIONS: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2 orally administered once weekly.
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