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)

Thomas Cash, Elizabeth Fox, Xiaowei Liu, Charles G. Minard, Joel M. Reid, Adrienne C. Scheck, Brenda J. Weigel, Cynthia Wetmore

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere29065
JournalPediatric Blood and Cancer
Volume68
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
We would like to acknowledge Bradley Hanberry, PhD, and the Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core for their assistance with the collection, processing, and storage of specimens for our correlative studies. We would like to acknowledge Eli Lilly and Company for supplying prexasertib and support of pharmacokinetic analysis. Research funding was provided by the NCI of the NIH under award number UM1CA228823 and the Cookies for Kids' Cancer Foundation. Dr. Reid was supported in part by Grant Number P30 CA015083 from the NCI.

Funding Information:
We would like to acknowledge Bradley Hanberry, PhD, and the Children's Healthcare of Atlanta and Emory University's Children's Clinical and Translational Discovery Core for their assistance with the collection, processing, and storage of specimens for our correlative studies. We would like to acknowledge Eli Lilly and Company for supplying prexasertib and support of pharmacokinetic analysis. Research funding was provided by the NCI of the NIH under award number UM1CA228823 and the Cookies for Kids' Cancer Foundation. Dr. Reid was supported in part by Grant Number P30 CA015083 from the NCI.

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

  • CHK1 inhibitor
  • CHK1/2
  • LY2606368
  • pediatric
  • phase 1
  • prexasertib

PubMed: MeSH publication types

  • Journal Article

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