Phase 1 study of OKI-179, an oral class 1-selective depsipeptide HDAC inhibitor, in patients with advanced solid tumors: Final results.
Authors: Jodi A. Kagihara, Bradley Corr, Jose Maria Pacheco, S. Lindsey Davis, Christopher Hanyoung Lieu, Sunnie S. Kim, Antonio Jimeno, Amy M. Heim, John A. DeMattei, Gilad Gordon, Todd A. Triplett, S. Gail Eckhardt, James D. Winkler, Anthony D. Piscopio, Jennifer Robinson Diamond
Journal: Journal of Clinical Oncology (2021)

3075 Background: OKI-179 is a novel, oral pro-drug analog of largazole, a compound in the romidepsin-depsipeptide class of natural products. OKI-006, the active metabolite of OKI-179, inhibits HDAC 1,2,3 (IC 50 = 1.2, 2.4, 2.0 nM, respectively), with no significant inhibition of Class IIa HDACs and has shown promising activity in preclinical models of solid tumors. We conducted a first-in-human dose escalation study of OKI-179 in patients with advanced solid tumors. Methods: Patients with advanced solid tumors, ECOG ≤1, normal QTc, and disease refractory to or with no available standard therapy options were treated with OKI-179 with either intermittent dosing (once daily for 4 days on 3 days off) or continuous dosing (once daily). Dose escalation was conducted using a standard 3+3 design. Pharmacokinetic (PK) and pharmacodynamic (PD) testing was performed at various time points after dosing. Results: As of Feb 4, 2021, 26 patients (19 female, 7 male) were enrolled with mean age of 63 (range 41-83). Patients received a median of 5 (range 1-11) prior lines of therapy and most common tumor types included pancreatic (N = 5), breast (N = 4), lung (N = 4), and ovarian cancer (N = 4). Twenty patients were treated in intermittent dosing cohorts from 30-450 mg. One DLT (Grade 2 [G2] thrombocytopenia) occurred in the 450 mg cohort which was expanded to 6 patients without subsequent DLTs. Six patients were treated in 2 continuous dosing cohorts of 200 mg and 300 mg. Two of 3 patients in the 300 mg cohort had DLTs of G3-4 thrombocytopenia and no DLTs were observed in 3 patients treated at 200 mg PO daily. The most common adverse events (AEs) were nausea (62%), fatigue (42%), anemia (39%), anorexia (27%), and vomiting (23%). These AE’s were G1-2 except for G3 anemia (12%), G3 fatigue (12%), and G3 anorexia (4%). No other G4-5 treatment-related AEs occurred. Median time on study was 79 days and best response was stable disease (SD) in 10 of 24 patients evaluable for efficacy (42%). Prolonged SD was observed in patients with platinum-resistant serous ovarian cancer (446 days) and adenoid cystic nasopharyngeal carcinoma (256 days). OKI-006 achieved consistent exposure with C max &gt; 2,000 ng/ml and AUC &gt; 8,000 hr*ng/ml, well above the targeted exposure for efficacy based on pre-clinical studies in murine models. T max was 2 hours and T 1/2 was 6-8 hours. OKI-179 treatment resulted in &gt; 3X increased T cell histone H3K9 and H3K27 acetylation within circulating PBMCs at doses of 180 - 450 mg. Conclusions: OKI-179 has a manageable safety profile, with thrombocytopenia being the on-target DLT. It has a favorable PK profile and demonstrated on-target PD effects at tolerable doses. The MTD and RP2D for OKI-179 was 450 mg daily for intermittent dosing and 200 mg daily for continuous dosing. Phase 2 studies are being designed, with a focus on combination with endocrine therapy in ER+ breast cancer and in NRAS-mutant melanoma. Clinical trial information: NCT03931681.