Publications by authors named "Hilary McElwaine-Johnn"

3 Publications

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Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors.

Clin Cancer Res 2021 May 4. Epub 2021 May 4.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

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 IC = 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, = 2; rectal adenocarcinoma, = 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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http://dx.doi.org/10.1158/1078-0432.CCR-21-0238DOI Listing
May 2021

A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE).

J Immunother Cancer 2019 01 28;7(1):20. Epub 2019 Jan 28.

START Madrid, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain.

Background: Enadenotucirev 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.

Methods: Sixty-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 × 10 and 1 × 10 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.

Results: Enadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 10 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.

Conclusions: This 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 × 10 vp.

Trial Registration: ( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.
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http://dx.doi.org/10.1186/s40425-019-0510-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348630PMC
January 2019

DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial.

Vaccine 2009 Apr 24;27(18):2506-12. Epub 2009 Feb 24.

PowderMed Ltd., Oxford Science Park, UK.

Background: We have developed a Trivalent DNA vaccine for influenza consisting of three plasmids expressing haemagglutinin from different seasonal influenza virus strains delivered using PMED (particle mediated epidermal delivery). We set out to determine whether this vaccine (with and without a molecular adjuvant DNA Encoded Immunostimulator-Labile Toxin (DEI-LT)) could protect subjects from a controlled influenza virus challenge.

Methods: Healthy adult subjects were screened for susceptibility to infection with influenza A/H3 Panama/2007/99 then vaccinated with 4microg Trivalent influenza DNA vaccine, 2microg Trivalent influenza DNA vaccine plus DEI-LT or placebo. Safety and serological responses to vaccination were assessed and on Day 56 subjects were challenged with A/H3 Panama/2007/99 virus.

Results: Vaccination with 4microg Trivalent or 2microg Trivalent/DEI-LT was well tolerated and induced antibody responses to two of the three influenza virus vaccine strains. Post challenge, subjects in the 4microg Trivalent group (N=27) showed reductions in disease symptoms and viral shedding compared to placebo (N=27), with an overall vaccine efficacy of 41% (95% confidence interval (CI)=?1.5, 67.7) for 'Any illness with or without fever' and 53% for 'Upper respiratory tract infection' (95% CI=8.0, 77.7).

Conclusion: It was concluded that PMED vaccination with 4microg Trivalent influenza DNA vaccine was safe and elicited immunological responses that protected human subjects from influenza; this is the first report of protection of human subjects from disease by DNA vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2009.02.061DOI Listing
April 2009