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

Abstract

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 × 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.

Results: Enadenotucirev 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.

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 × 1012 vp.

Trial registration: ( ClinicalTrials.gov Identifier: NCT02028442 ). Trial registration date: 07 January 2014 - Retrospectively registered.

Keywords: Clinical trials; Enadenotucirev; Epithelial solid tumor; Intravenous; Oncolytic adenovirus; Pharmacokinetics and pharmacodynamics.

Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the institutional review board of each participating center and was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation of Good Clinical Practice guidelines. All patients provided written informed consent before study entry.

Consent for publication

Not applicable.

Competing interests

J-PM, RS, SR, ID, LD, and KG have no potential conflicts of interest to declare.

CW-B and GP were employees of PsiOxus Therapeutics Limited at the time of the study.

SA, BC, KF, and HM-J are employees of PsiOxus Therapeutics Limited.

JB is an employee, company director, and shareholder of PsiOxus Therapeutics Limited.

EC is a paid employee of START Madrid and HM Hospitales Group and is president and founder of Foundation INTHEOS. EC has stock and/or ownership interests in START Madrid, OncoArt Associated and International Cancer Consultants and has received honoraria from HM Hospitales Group and travel/accommodation expenses from Roche/Genentech. EC has received research-related funding from AstraZeneca, Novartis, BeiGene and START Madrid. EC has received consulting and/or advisory fees from Abbvie, Amcure, AstraZeneca, Celgene, EUSA Pharma, GLG, Guidepoint Global, Janssen-Cilag, Nanobiotix, Novartis, Pfizer, PsiOxus Therapeutics Limited, Roche/Genentech, Seattle Genetics, SERVIER, and START Madrid.

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Figures

Fig. 1

Patient disposition and study design. The phase 1 single-cycle dose escalation and dose expansion stages of EVOLVE were designed to determine the MTD of enadenotucirev, given in one cycle (one administration on days 1, 3, and 5 and an end-of-study visit 56 days after the last administration of enadenotucirev). a The phase 1a repeat cycle stage comprised up to four 21-day cycles and an end-of-study visit 28 days after the last administration of enadenotucirev. b The phase 1b component was initiated to select a suitable schedule and dose for repeat cycles of enadenotucirev in patients with mCRC or UCC. Phase 1b comprised up to six 21-day cycles, ending with an end-of-study visit 28 days after the last administration of enadenotucirev. Please refer to the study design and dosing and patient enrollment sections of the methods and patient demographics section of the results for full details of the enrollment into this phase. c Overall study design of the EVOLVE study. CRC colorectal cancer, ECOG Eastern Cooperative Oncology Group, EVOLVE EValuating OncoLytic Virus Efficacy, IV intravenous, mCRC metastatic colorectal cancer, MTD maximum tolerated dose, Q1W weekly schedule, Q3W 3-weekly schedule, UCC urothelial cell carcinoma, vp viral particle(s). aOne participant later received one additional cycle of treatment. bThree participants received one or more additional cycles of treatment. cOne participant also had inadequate bone marrow function

Fig. 2

Blood viral kinetics and mean enadenotucirev concentration in blood by cohort. a Theoretical day 1 kinetics of enadenotucirev. b Box plot showing the mean (and 95% CI) half-life across dosing cohorts of EVOLVE phase 1a on dosing days 1, 3, and 5. c Fold change increase in Cmax across dose administrations. The red box represents outlier box plot quantile analysis, and the green diamond represents mean and 95% CI across dosing cohorts of EVOLVE phase 1a on dosing days 1, 3, and 5. d Mean (± SD) enadenotucirev blood concentration by cohort. CI confidence interval, Cmax maximum serum concentration, EOI end of infusion, EVOLVE EValuating OncoLytic Virus Efficacy, LOQ level of quantification, SD standard deviation, vp viral particle(s)

Fig. 3

Post-infusion viral shedding during phase 1a. a Mean buccal shedding as quantified by qPCR with solid bars representing the mean and error bars representing the range observed. The number of patients in whom buccal shedding was detected (N; > 0 vp/μL) is represented by N. The total number of samples represents the number of samples taken at each time point. The proportion positive is the percentage of samples in which buccal shedding was detected across all cohorts. b Mean rectal shedding as quantified by qPCR with bars representing the mean and error bars the range observed. The number of patients in whom rectal shedding was detected (N; > 0 vp/μL) is represented by N. The total number of samples represents the number of samples taken at each time point. The proportion positive is the percentage of samples in which buccal shedding was detected across all cohorts. LOQ level of quantification, N number, qPCR quantitative polymerase chain reaction, vp viral particle(s)

Fig. 4

Summary of anti-enadenotucirev antibody response. Scatter plot of anti-enadenotucirev antibody titer over time, with the blue line representing the moving mean

Fig. 5

Cytokine levels in the blood by infusion dose during phase 1a. a Mean concentration of IFN-γ by dose. b Mean concentration of IL-6 by dose. c Mean concentration of MCP-1 by dose. d Mean concentration of TNF-α by dose. e Frequency of TEAEs (including any of chills, influenza-like illness, and pyrexia) per dose occurring within 24 h of infusion on cycle 1, day 1 or following infusion on day 3/5. IFN interferon, IL interleukin, MCP monocyte chemoattractant protein, TEAE treatment-emergent adverse event, TNF tumor necrosis factor, vp viral particle(s)