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)

Andrew Bukowinski, Bill Chang, Joel M. Reid, Xiaowei Liu, Charles G. Minard, Jane B. Trepel, Min Jung Lee, Elizabeth Fox, Brenda J. Weigel

Research output: Contribution to journalArticlepeer-review

Abstract

Background: 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 I trial 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 system (CNS) malignancies. Methods: 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. Results: Twenty-one eligible patients’ median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m2 dose level and 15 were treated in 4 mg/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 three-fold 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. Conclusions: 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 PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2 orally administered once weekly.

Original languageEnglish (US)
Article numbere28892
JournalPediatric Blood and Cancer
Volume68
Issue number4
DOIs
StatePublished - Apr 2021

Bibliographical note

Funding Information:
Jane B. Trepel has received research funding from Syndax Pharmaceuticals through a Cooperative Research and Development Agreement with her Institution. The remaining authors declare that there is no conflict of interest.

Funding Information:
We would like to thank Alina Stout, Lorraine Sarmiento, Blanca Herrera, and Thalia Beeles from Children's Oncology Group Operations Center for their contributions to this study. We wish to also thank Dr Suman Malempati for the initial implementation of this trial. This study was funded under National Institutes of Health (NIH) award number UM1 CA228823 as well as NIH Award ZIC SC 006743 to Jane B. Trepel and the Cookies for Kids’ Cancer Foundation ( www.cookiesforkidscancer.org ). Joel M. Reid was supported in part by Grant Number P30 CA015083 from the National Cancer Institute (NCI).

Funding Information:
National Institutes of Health (NIH), Award Numbers: UM1 CA228823, ZIC SC 006743; National Cancer Institute (NCI), Grant Number: P30 CA015083; Cookies for Kids’ Cancer Foundation

Funding Information:
We would like to thank Alina Stout, Lorraine Sarmiento, Blanca Herrera, and Thalia Beeles from Children's Oncology Group Operations Center for their contributions to this study. We wish to also thank Dr Suman Malempati for the initial implementation of this trial. This study was funded under National Institutes of Health (NIH) award number UM1 CA228823 as well as NIH Award ZIC SC 006743 to Jane B. Trepel and the Cookies for Kids? Cancer Foundation (www.cookiesforkidscancer.org). Joel M. Reid was supported in part by Grant Number P30 CA015083 from the National Cancer Institute (NCI).

Publisher Copyright:
© 2021 Wiley Periodicals LLC

Keywords

  • Ewing sarcoma
  • glioma low grade
  • neuro-oncology
  • oncology general
  • osteosarcoma
  • pediatric hematology oncology
  • pediatric oncology
  • phase 1 clinical trial agents
  • phase 1 study
  • rhabdomyosarcoma

PubMed: MeSH publication types

  • Journal Article

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