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Invest New Drugs. 2018 Oct;36(5):877-885. doi: 10.1007/s10637-018-0582-0. Epub 2018 Mar 9.

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

Author information

1
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
2
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
3
Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
5
Department of Hematology-Oncology, Center for Hematologic Malignancy, National Cancer Center, Goyang-si, Republic of Korea.
6
Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea.
7
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. csuh@amc.seoul.kr.

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.

KEYWORDS:

Histone deacetylase inhibitor; Lymphoma; Multiple myeloma; Pharmacodynamics; Pharmacokinetics

PMID:
29520651
DOI:
10.1007/s10637-018-0582-0
[Indexed for MEDLINE]

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