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, Jinseok 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

Histone Deacetylase Inhibitors
Multiple Myeloma
Lymphoma
Maximum Tolerated Dose
Pharmacokinetics
Therapeutics
Neutropenia
Histones
Acetylation
Thrombocytopenia
Area Under Curve
Blood Cells
Neoplasms
Safety

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Cho, Hyungwoo ; Yoon, Dok Hyun ; Kim, Kyu pyo ; Bae, Kyun Seop ; Kim, Won Seog ; Eom, Hyeon Seok ; Kim, Jinseok ; Hong, Jung Yong ; Kim, Seok Jin ; Lee, Hyewon ; Kim, Soo Jeong ; Suh, Cheolwon. / Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. In: Investigational New Drugs. 2018 ; Vol. 36, No. 5. pp. 877-885.
@article{2d25f09b5c694e0fb9dddbfab5652f26,
title = "Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy",
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.",
author = "Hyungwoo Cho and Yoon, {Dok Hyun} and Kim, {Kyu pyo} and Bae, {Kyun Seop} and Kim, {Won Seog} and Eom, {Hyeon Seok} and Jinseok Kim and Hong, {Jung Yong} and Kim, {Seok Jin} and Hyewon Lee and Kim, {Soo Jeong} and Cheolwon Suh",
year = "2018",
month = "10",
day = "1",
doi = "10.1007/s10637-018-0582-0",
language = "English",
volume = "36",
pages = "877--885",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "5",

}

Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy. / Cho, Hyungwoo; Yoon, Dok Hyun; Kim, Kyu pyo; Bae, Kyun Seop; Kim, Won Seog; Eom, Hyeon Seok; Kim, Jinseok; Hong, Jung Yong; Kim, Seok Jin; Lee, Hyewon; Kim, Soo Jeong; Suh, Cheolwon.

In: Investigational New Drugs, Vol. 36, No. 5, 01.10.2018, p. 877-885.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Phase I study of CKD-581, a pan-histone deacetylase inhibitor, in patients with lymphoma or multiple myeloma refractory to standard therapy

AU - Cho, Hyungwoo

AU - Yoon, Dok Hyun

AU - Kim, Kyu pyo

AU - Bae, Kyun Seop

AU - Kim, Won Seog

AU - Eom, Hyeon Seok

AU - Kim, Jinseok

AU - Hong, Jung Yong

AU - Kim, Seok Jin

AU - Lee, Hyewon

AU - Kim, Soo Jeong

AU - Suh, Cheolwon

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85043373471&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043373471&partnerID=8YFLogxK

U2 - 10.1007/s10637-018-0582-0

DO - 10.1007/s10637-018-0582-0

M3 - Article

C2 - 29520651

AN - SCOPUS:85043373471

VL - 36

SP - 877

EP - 885

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 5

ER -