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BackgroundEnadenotucirev is a chimeric adenovirus with demonstrated preclinical tumor-selective cytotoxicity and a short half-life. Further clinical mechanism of action data showed that enadenotucirev can gain access to and replicate within different types of epithelial tumors. This phase 1 dose escalation study assessed intravenous (IV) dose escalation with enadenotucirev to establish the maximum tolerated dose (MTD) and subsequently identify a suitable schedule for repeated cycles.MethodsSixty-one patients with advanced epithelial tumors unresponsive to conventional therapy were enrolled and received enadenotucirev monotherapy as part of this study. During the phase 1a dose escalation (n = 22) and expansion (n = 9), delivery of enadenotucirev between 1 × 1010 and 1 × 1013 viral particles (vp) on days 1, 3, and 5 (single cycle) was used to determine an appropriate MTD. Subsequent treatment cohorts (phase 1a, n = 6 and phase 1b, n = 24) examined the feasibility of repeated dosing cycles in either 3-weekly or weekly dosing regimens.ResultsEnadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 1012 vp, irrespective of infusion time or dosing schedule. The most commonly reported treatment-emergent adverse events (TEAEs) of grade 3 or higher were hypoxia, lymphopenia, and neutropenia. The frequency of all TEAEs (notably pyrexia and chills) was highest within 24 h of the first enadenotucirev infusion and decreased upon subsequent dosing. Additionally, delivery of three doses of enadenotucirev over 5 days optimized pharmacokinetic and chemokine profiles in the circulation over time.ConclusionsThis study provides key clinical data in patients with solid epithelial tumors following treatment with IV enadenotucirev monotherapy and supports further investigation of enadenotucirev in combination with other therapeutic agents at doses up to the MTD of 3 × 1012 vp.Trial registration(ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0510-7) contains supplementary material, which is available to authorized users.

Purpose: Inhibition of histone deacetylase 6 (HDAC6) is predicted to deliver both direct antitumor activity and modulation of the antitumor immune response. This study describes the development of a novel HDAC6 inhibitor. Patients and Methods: KA2507 was characterized in HDAC biochemical and cellular target engagement assays and in preclinical efficacy models of melanoma and colorectal cancer. In a phase I study, KA2507 was administered orally using a 3+3 dose-escalation design (NCT03008018). Results: KA2507 is a potent and selective inhibitor of HDAC6 (biochemical IC50 = 2.5 nmol/L). Preclinical models demonstrated antitumor efficacy in syngeneic tumor-bearing mice, with translational studies highlighting modulation of the antitumor immune response. Twenty patients were treated in a phase I study. KA2507 was well tolerated; dose-limiting toxicity was not observed up to the maximum dose administered. Pharmacokinetic profiling supported twice-daily oral dosing. Pharmacodynamic analysis demonstrated selective HDAC6 target engagement in peripheral blood cells, free from off-target class I HDAC activity. Stable disease was the best clinical response (7 patients). Three of these patients (adenoid cystic carcinoma, n = 2; rectal adenocarcinoma, n = 1) had prolonged disease stabilization that lasted for 16.4, 12.6, and 9.0 months, respectively. Conclusions: KA2507 is a potent and selective inhibitor of HDAC6 showing antitumor efficacy and immune modulatory effects in preclinical models. In a phase I study, KA2507 showed selective target engagement, no significant toxicities, and prolonged disease stabilization in a subset of patients. Further clinical studies of KA2507 are warranted, as a single agent or, preferably, combined with other immuno-oncology drugs.

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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.