Cash, Thomas F.

AbstractBackgroundPrexasertib (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.MethodsPrexasertib was administered intravenously (i.v.) 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 and TP53) of prexasertib activity.ResultsThirty patients were enrolled; 25 were evaluable. The 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 three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80‐150 mg/m2 dose range.ConclusionsAlthough the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28‐day cycle was determined to be the RP2D.

AbstractBackgroundThe prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES.MethodsPatients had localized ES and were treated on two consecutive protocols using five‐drug chemotherapy (INT‐0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event‐free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log‐rank test, and modeled using Cox multivariate regression.ResultsPatients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS.ConclusionClinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.