Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors

Abstract

Background Dysregulation of histone deacetylases (HDACs) is common in cancer and is critical to the development and progression of the majority of tumors. This first-in-human Phase Ia study assessed the safety, efficacy, and pharmacokinetics (PK) of OBP-801, a cyclic depsipeptide class I HDAC inhibitor. Methods Adult patients with advanced solid tumors were treated in 3 dose cohorts (1.0 mg/m 2 , 2.0 mg/m 2 or 2.8 mg/m 2 ) of OBP-801 that was administered via intravenous infusion weekly. Initially, an accelerated titration design was used that was followed by a 3 + 3 dose escalation strategy. Primary objective was assessment of safety. Secondary objectives included determination of PK and objective response rate. Results Seventeen patients were enrolled, of which 8 patients were evaluable for efficacy. Drug-related ≥ Grade 3 treatment-emergent adverse events included abdominal pain, anemia, fatigue, gamma glutamyl-transferase increase, hypertriglyceridemia and vomiting. No dose-limiting toxicity was observed in the 1.0 mg/m 2 cohort. The PK data showed that OBP-801 and its active metabolite OBP-801-SH exposure increased proportionally and more than proportionally, respectively. No accumulation of either agent was noticed after repeat administration. Best response was stable disease (37.5%), with one patient each in the three cohorts. Conclusion Further investigations of the OBP-801 1.0 mg/m 2 dose will be needed to better understand the efficacy of the agent, either alone or in combination. Trial registration: NCT02414516 (ClinicalTrials.gov) registered on April 10, 2015.

Marine Organisms as a Prolific Source of Bioactive Depsipeptides

“…The marine cyanobacteria Symploca and Lyngbya spp. are the major producers of linear depsipeptides ( 1 – 27 , Figure 2 ) [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Grassystatins D–F ( 1–3 ) containing statine units have strong aspartic protease inhibitory activity preferentially targeting cathepsins D and E [ 14 ].…”

“…Depsipeptides are an important group of polypeptides simultaneously containing ester and amide bonds, and they display a wide variety of biological properties [ 2 , 3 ]. A number of naturally occurring depsipeptides have been successfully developed as new drugs or are being evaluated in clinical trials, such as the antitumor agents romidepsin [ 4 , 5 ], plitidepsin (aplidine) [ 6 , 7 ], kahalalide F [ 8 , 9 ] and OBP-801 (spiruchostatin A) [ 10 ]. Generally, these substances are divided into two groups, namely, cyclic and non-cyclic, of which the former tends to display excellent bioactivity [ 11 , 12 ].…”