Abstract CT151: Phase I study of KA2507, a selective HDAC6 inhibitor, in patients with relapsed or refractory solid tumors
Authors: Tsimberidou Apostolia M. , Beer Philip , Bendall Jennifer , Dow James , King Justine , McElwaine-Johnn Hilary , Wistuba Ignacio I. 
Published: September 2020

Abstract
Background: KA2507 is a potent and selective small molecule inhibitor of HDAC6. Inhibition of HDAC6 elicits both cell intrinsic and extrinsic anti-cancer activity. HDAC6 is also involved in the regulation of the co-inhibitory molecule programmed death ligand 1 (PD-L1). We conducted a first-in-human (FIH) study to assess the pharmacokinetics, safety and tolerability of KA2507 monotherapy in patients with advanced cancer with preliminary assessment of any antitumor activity. Methods: In this FIH, dose-escalation phase I study, patients (pts) with advanced metastatic cancer who had failed standard therapy were enrolled. KA2507 was administered orally at escalating doses of 50 mg QD, 100 mg QD, 200 mg QD, 200 mg BID, 400 mg BID, and 800 mg BID (1 cycle = 28 days). A “3+3” design was used. PD assessment was performed measuring changes in acetylated tubulin and histone in peripheral blood cells post dosing. Response was assessed by RECIST 1.1 criteria. (www.clinicaltrials.gov, NCT03008018). Results: Twenty pts with various tumor types commenced treatment from Aug 2017 to Aug 2019. The median age was 56 years (27-78 years) and 13 were males. The most common tumor types were adenoid cystic carcinoma (ACC, n=6) and colorectal cancer (n=4). Seventeen of 20 (85%) pts reported at least one treatment emergent adverse event (AE). Five (25%) pts across all dose cohorts reported treatment related AEs, considered to be at least possibly related to treatment (all Grade 1). No treatment related hematologic toxicities were noted. No dose-limiting toxicity was observed up to the maximum dose level tested. PK analysis demonstrated that the PK parameters of KA2507 were similar across all doses tested and after single and repeated oral dosing, with rapid absorption following oral administration, Tmax ~2 h; t½ ~3 h; dose-proportional exposure; low accumulation. PD assessment demonstrated that the fold-increase in acetylation of tubulin in T-cells increased with exposure (P=0.02), with no significant effect on acetylated histone (P=0.4). Seven (35%) of these heavily pre-treated pts with advanced cancer had stable disease (SD). One pt with ACC had SD and remained on study for 18 cycles, and another pt for 12+ cycles. No objective response was noted. Discussion: KA2507 was well tolerated at all doses tested (up to 800 mg BID) with evidence of selective target engagement at all exposure levels. The dose was not limited by the AEs previously reported in clinical trials of other, less selective HDAC6 inhibitors. A dose of 800 mg BID has been identified for further development and is considered the maximum feasible dose, representing a dose that is well tolerated, achieving exposure that is invariably above the biologically active level identified in pre-clinical syngeneic efficacy models, yet not exceeding the human equivalent dose of the NOAEL in GLP-toxicology and maintaining selectivity for HDAC6. A dose expansion cohort to further investigate this dose is planned.
Citation Format: Apostolia M. Tsimberidou, Philip Beer, Jennifer Bendall, James Dow, Justine King, Hilary McElwaine-Johnn, Ignacio I. Wistuba. Phase I study of KA2507, a selective HDAC6 inhibitor, in patients with relapsed or refractory solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT151.