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

• Published in: Investigational new drugs Vol. 40; no. 2; pp. 300 - 307
• Main Authors: Heath, Elisabeth I., Weise, Amy, Vaishampayan, Ulka, Danforth, Dailan, Ungerleider, Richard S., Urata, Yasuo
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2022; Springer Nature B.V
• Subjects: Adult; Anemia; Depsipeptides - adverse effects; Histone deacetylase; Histone Deacetylase Inhibitors - adverse effects; Histones; Humans; Hypertriglyceridemia; Inhibitors; Intravenous administration; Intravenous infusion; Maximum Tolerated Dose; Medicine; Medicine & Public Health; Metabolites; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Pain; Patients; Peptides, Cyclic - adverse effects; Pharmacokinetics; Pharmacology/Toxicology; Phase I Studies; Safety; Solid tumors; Titration; Toxicity; Tumors; Vomiting; OBP-801; Phase Ia; Solid tumors; Histone deacetylase inhibitors
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01180-9

Summary 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.