A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children’s Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515)

Cash T, Fox E, Liu X, Minard CG, Reid JM, Scheck AC, Weigel BJ, Wetmore C. A phase 1 study of prexasertib (LY2606368), a CHK1/2 inhibitor, in pediatric patients with recurrent or refractory solid tumors, including CNS tumors: A report from the Children’s Oncology Group Pediatric Early Phase Clinical Trials Network (ADVL1515). Pediatr Blood Cancer. 2021 Sep;68(9):e29065. doi: 10.1002/pbc.29065. Epub 2021 Apr 21. PMID: 33881209; PMCID: PMC9090141.

Prexasertib (LY2606368) is a novel, second generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a Phase 1 trial of prexasertib to estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors. Prexasertib was administered intravenously (IV) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2, were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1, TP53) of prexasertib activity. Thirty patients were enrolled; twenty-five were evaluable. Median age was 9.5 years (range: 2–20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (>10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in 3 patients for 5 cycles (hepatocellular carcinoma), 3 cycles (ependymoma), and 5 cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80–150 mg/m2 dose range. While the MTD of prexasertib was not defined by this study, 150 mg/m2 administered IV on day 1 and 15 of a 28-day cycle was determined to be the RP2D.