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/m2, 2.0 mg/m2 or 2.8 mg/m2) 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/m2 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/m2 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.
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The datasets analyzed during the study are available from the corresponding author on reasonable request and after approval from Oncolys Biopharma Inc., Tokyo, Japan.
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All funding was provided by Oncolys BioPharma Inc.
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The study was funded by Oncolys Biopharma Inc., Tokyo, Japan.
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EIH was primarily responsible for the study design, execution and supervision, as well as of writing of the manuscript. All authors contributed to the writing and/or revision of the manuscript, and approved its submission.
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The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization/Good Clinical Practice (ICH/GCP), applicable regulatory requirements and the policy on bioethics. This study was approved by the Wayne State University Institutional Review Board.
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has received research funding from Oncolys BioPharma, Inc. She has served on advisory boards for Oncolys BioPharma, Inc., and Theradex Oncology. DD and RSU were both employees of Theradex Oncology during the period of the study. YU was an employee of Oncolys BioPharma, Inc. during the period of the study. AW and UV have nothing to declare.
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Heath, E.I., Weise, A., Vaishampayan, U. et al. Phase Ia dose escalation study of OBP-801, a cyclic depsipeptide class I histone deacetylase inhibitor, in patients with advanced solid tumors. Invest New Drugs 40, 300–307 (2022). https://doi.org/10.1007/s10637-021-01180-9
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DOI: https://doi.org/10.1007/s10637-021-01180-9