A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN)

Bukowinski A, Chang B, Reid JM, Liu X, Minard CG, Trepel JB, Lee MJ, Fox E, Weigel BJ. A phase 1 study of entinostat in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1513, Pediatric Early Phase-Clinical Trial Network (PEP-CTN). Pediatr Blood Cancer. 2021 Apr;68(4):e28892. doi: 10.1002/pbc.28892. Epub 2021 Jan 12. PMID: 33438318; PMCID: PMC9176707.

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 1trial 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 systems malignancies. 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. Twenty-one eligible patients median (range) age 14 (6–20). Six subjects were treated at 3mg/m2 dose level and fifteen were treated in 4mg/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 threefold 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. 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 pharmacokinetics and pharmacodynamics, the R2PD in pediatric patients with solid tumors is 4mg/m2 orally administered once weekly.