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Investigational New Drugs

, Volume 36, Issue 5, pp 877–885 | Cite as

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
PHASE I STUDIES
  • 145 Downloads

Summary

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.

Keywords

Lymphoma Multiple myeloma Histone deacetylase inhibitor Pharmacokinetics Pharmacodynamics 

Notes

Acknowledgments

This study was supported by Chong Kun Dang Pharm.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consents were obtained from all participants included in the study.

Supplementary material

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Table S1 (DOCX 26 kb)
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Table S2 (DOCX 26 kb)
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Supplementary Fig. S1

Linear regression analysis of CKD-581 dose and Cmax (a, day 1; b, day 15), AUClast (c, day 1; d, day 15), and AUCinf (e, day 1; f, day 15) (JPG 2.06 mb)

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High resolution image (TIFF 867 kb)
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Supplementary Fig. S2

Linear regression analysis of M2 dose and Cmax (a, day 1; b, day 15), AUClast (c, day 1; d, day 15), and AUCinf (e, day 1; f, day 15) (GIF 60 kb)

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High resolution image (TIFF 938 kb)
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Supplementary Fig. S3

Linear regression analysis of M4 dose and Cmax (a, day 1; b, day 15), AUClast (c, day 1; d, day 15), and AUCinf (e, day 1; f, day 15) (GIF 65 kb)

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High resolution image (TIFF 1015 kb)
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Supplementary Fig. S4

Kruskal–Wallis analysis of CKD-581 dose and T1/2 (a, day 1; b, day 15), CL (c, day 1; d, day 15), Fe (e, day 1; f, day 15), and Vd (g, day 1; h, day 15) (GIF 85 kb)

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High resolution image (TIFF 1806 kb)
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Supplementary Fig. S5

Kruskal–Wallis analysis of CKD-581 dose and M2/parent ratio. AUClast (a, day 1; b, day 15) and AUCinf (c, day 1; d, day 15) (GIF 42 kb)

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High resolution image (TIFF 868 kb)
10637_2018_582_Fig7_ESM.gif (43 kb)
Supplementary Fig. S6

Kruskal–Wallis analysis of CKD-581 dose and M4/parent ratio. AUClast (a, day 1; b, day 15) and AUCinf (c, day 1; d, day 15) (GIF 42 kb)

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High resolution image (TIFF 910 kb)
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Supplementary Fig. S7

Kruskal–Wallis analysis of CKD-581 dose and M4/M2 ratio. AUClast (a, day 1; b, day 15) and AUCinf (c, day 1; d, day 15) (GIF 46 kb)

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High resolution image (TIFF 951 kb)
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Supplementary Fig. S8

Fold increase in histone H3 acetylation (a) and histone H4 acetylation (b) (GIF 69 kb)

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High resolution image (TIFF 1626 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Hyungwoo Cho
    • 1
  • Dok Hyun Yoon
    • 2
  • Kyu-pyo Kim
    • 2
  • Kyun-Seop Bae
    • 3
  • Won Seog Kim
    • 4
  • Hyeon-Seok Eom
    • 5
  • Jin Seok Kim
    • 6
  • Jung Yong Hong
    • 2
  • Seok Jin Kim
    • 4
  • Hyewon Lee
    • 5
  • Soo-Jeong Kim
    • 6
  • Cheolwon Suh
    • 2
  1. 1.Department of Internal MedicineAsan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Department of OncologyAsan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
  3. 3.Department of Clinical Pharmacology and TherapeuticsAsan Medical Center, University of Ulsan College of MedicineSeoulRepublic of Korea
  4. 4.Division of Hematology–Oncology, Department of Medicine, Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  5. 5.Department of Hematology–Oncology, Center for Hematologic MalignancyNational Cancer CenterGoyang-siRepublic of Korea
  6. 6.Division of Hematology, Department of Internal MedicineYonsei University College of Medicine, Severance HospitalSeoulRepublic of Korea

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