التفاصيل البيبلوغرافية
| العنوان: |
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. |
| المؤلفون: |
Schreiber, Anna R., Kagihara, Jodi A., Corr, Bradley R., Davis, S. Lindsey, Lieu, Christopher, Kim, Sunnie S., Jimeno, Antonio, Camidge, D. Ross, Williams, Jud, Heim, Amy M., Martin, Anne, DeMattei, John A., Holay, Nisha, Triplett, Todd A., Eckhardt, S. Gail, Litwiler, Kevin, Winkler, James, Piscopio, Anthony D., Diamond, Jennifer R. |
| المصدر: |
Cancers; Jan2024, Vol. 16 Issue 1, p91, 15p |
| مصطلحات موضوعية: |
THERAPEUTIC use of antineoplastic agents, DRUG dosage, DRUG tolerance, CLINICAL trials, NAUSEA, TIME, PROTEIN kinase inhibitors, TREATMENT duration, CANCER patients, DESCRIPTIVE statistics, RESEARCH funding, TUMORS, HISTONE deacetylase, FATIGUE (Physiology), THROMBOCYTOPENIA, DRUG toxicity, PATIENT safety, CHEMICAL inhibitors |
| مستخلص: |
Simple Summary: Histone deacetylase (HDAC) inhibitors are anti-cancer agents that have demonstrated efficacy in hematologic malignancies; however, the utility of available agents is limited, owing to narrow therapeutic indices and suboptimal isoform selectivity. Bocodepsin (OKI-179) is a novel, orally bioavailable, Class I-targeting depsipeptide HDAC inhibitor with promising anti-cancer activity in preclinical solid tumor models. In this first-in-human phase I clinical study, we report the safety and tolerability of OKI-179 administered orally daily with intermittent and continuous dosing schedules. OKI-179 was well tolerated with low rates of high-grade adverse events, supporting the potential for the successful combination of OKI-179 with other targeted anti-cancer agents. OKI-179 is currently being investigated in combination with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma. (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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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