First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors.

Autor: Schreiber AR; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Kagihara JA; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.; Division of Medical Oncology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA., Corr BR; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Davis SL; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Lieu C; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Kim SS; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Jimeno A; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Camidge DR; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Williams J; OnKure, Inc., Boulder, CO 80301, USA., Heim AM; OnKure, Inc., Boulder, CO 80301, USA., Martin A; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., DeMattei JA; OnKure, Inc., Boulder, CO 80301, USA., Holay N; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA., Triplett TA; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.; Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA., Eckhardt SG; Livestrong Cancer Institutes, Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.; Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77054, USA., Litwiler K; OnKure, Inc., Boulder, CO 80301, USA., Winkler J; OnKure, Inc., Boulder, CO 80301, USA., Piscopio AD; OnKure, Inc., Boulder, CO 80301, USA., Diamond JR; Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2023 Dec 23; Vol. 16 (1). Date of Electronic Publication: 2023 Dec 23.
DOI: 10.3390/cancers16010091
Abstrakt: (1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients ( n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11-447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.
Databáze: MEDLINE
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