Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy

Hyungwoo Cho, Dok Hyun Yoon, Kyu pyo Kim, Kyun Seop Bae, Won Seog Kim, Hyeon Seok Eom, Jin Seok Kim, Jung Yong Hong, Seok Jin Kim, Hyewon Lee, Soo Jeong Kim, Cheolwon Suh

Research output: Contribution to journalArticle

Abstract

Background The objective of this study was to assess the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics, and anti-tumor efficacy of CKD-581, a novel pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma (MM) refractory to standard therapy. Methods In this phase I study, CKD-581 was intravenously administered on days 1, 8, and 15 of a 28-day cycle. A standard 3 + 3 cohort design was used to determine the MTD. Acetylated histones H3 and H4 in peripheral blood mononuclear cells were measured for pharmacodynamic assessment in a subpopulation of patients. Results Thirty-nine patients were treated with CKD-581 at 9 dose levels from 10 mg/m2 to 210 mg/m2. The DLTs were grade 3 neutropenia that delayed the treatment for >2 weeks (one patient at a dose of 50 mg/m2) and grade 4 thrombocytopenia (two patients at a dose of 210 mg/m2). The MTD of CKD-581 was 160 mg/m2. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (n = 5, 12.8%) and neutropenia (n = 2, 5.1%). The peak concentration and area under the curve values for CKD-581 increased in proportion to the dose, indicating linear pharmacokinetics. A partial response was observed in 2 patients (5.6%), and stable disease was observed in 16 (44.4%) patients. In the pharmacodynamic evaluation, acetylation of H3 and H4 was observed at all doses of ≥50 mg/m2. Conclusion CKD-581 was well tolerated by the patients with lymphoma or MM refractory to standard therapy. It exhibited dose-proportional pharmacokinetics and modest anti-tumor efficacy.

Original languageEnglish
Pages (from-to)877-885
Number of pages9
JournalInvestigational New Drugs
Volume36
Issue number5
DOIs
Publication statusPublished - 2018 Oct 1

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Cho, H., Yoon, D. H., Kim, K. P., Bae, K. S., Kim, W. S., Eom, H. S., Kim, J. S., Hong, J. Y., Kim, S. J., Lee, H., Kim, S. J., & Suh, C. (2018). Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. Investigational New Drugs, 36(5), 877-885. https://doi.org/10.1007/s10637-018-0582-0