| Autor: |
Anna R. Schreiber, Jodi A. Kagihara, Bradley R. Corr, S. Lindsey Davis, Christopher Lieu, Sunnie S. Kim, Antonio Jimeno, D. Ross Camidge, Jud Williams, Amy M. Heim, Anne Martin, John A. DeMattei, Nisha Holay, Todd A. Triplett, S. Gail Eckhardt, Kevin Litwiler, James Winkler, Anthony D. Piscopio, Jennifer R. Diamond |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Cancers, Vol 16, Iss 1, p 91 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2072-6694 |
| DOI: |
10.3390/cancers16010091 |
| Popis: |
(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: |
Directory of Open Access Journals |
| Externí odkaz: |
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