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)

Abstract

Background: 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.

Methods: Prexasertib 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.

Results: Thirty 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.

Conclusions: Although 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.

Trial registration: ClinicalTrials.gov NCT02808650.

Keywords: CHK1 inhibitor; CHK1/2; LY2606368; pediatric; phase 1; prexasertib.

© 2021 Wiley Periodicals LLC.

Figures

Figure 1.. Effect of Prexasertib on Absolute Neutrophil Count (ANC) during Cycle 1 Across All Dose Levels.

Different line colors represent individual patients.

Figure 2.. Prexasertib Pharmacokinetics in Pediatric Patients with Recurrent or Refractory Solid and CNS Tumors.

The mean plasma concentration as a function of time for patients treated with 150 mg/m2 of prexasertib (A), mean AUC0−∞ for each dose level with horizontal line on the plot representing median AUC0–72h value (1896 ng*hr/ml) predicted for efficacy based on the Calu-6 preclinical PK/PD model (B), mean plasma clearance for each dose level (C), and plasma clearance as a function of body surface area (D). Error bars represent the standard deviation for each observation.