Abstract TPS2668

A multicenter, open-label, first in human study of an oncolytic viral vector expressing an agonistic anti-CD40 antibody (NG-350A) in patients with epithelial tumors (FORTITUDE)

Aung Naing1, Ecaterina E Ileana Dumbrava1 , Ravi Murthy1; Funda Meric-Bernstam1, Andrew Fox2,David Krige2, Jo Carter2, Brian Champion2, Paul Cockle2, Barbara Koetz2, Hilary McElwaine-Johnn2

1 MD Anderson Cancer Center, Houston, USA; 2 PsiOxus Therapeutics Ltd, Abingdon, United Kingdom

• Clinical conduct of the study was initiated in February 2019• Dose escalation is ongoing with 3 patients enrolled• Conduct planned in six US-based clinical sites• ClinicalTrials.gov identifier: NCT03852511

• Phase I, first in human study to evaluate the safety, tolerability and preliminary efficacy of NG-350A together with virus kinetics, immunogenicity and other pharmacodynamic effects of NG-350A in patients with advanced or metastatic epithelial tumors

• Phase Ia of the study is a dose escalation and safety expansion phase investigating NG-350A administration by intratumoral injection (Day 1 only) and intravenous infusion (one cycle of treatment consisting of intravenous infusion on Days 1, 3 and 5)

• Phase Ib of the study is to investigate efficacy in up to three separate efficacy cohorts of patients with epithelial tumor types

1 Kuhn (2008) Directed evolution generates a novel oncolytic virusfor the treatment of colon cancer. PLoS One 3, e2409.2 Calvo (2014) Annals of Oncology, Volume 25, Supplement 4, 2014(1064P)

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Key Inclusion Criteria− Confirmed diagnosis of advanced or metastatic epithelial

cancer (carcinoma or adenocarcinoma) that has relapsed from,or is refractory to, standard treatment, or for which no standardtreatment is available

− ECOG performance status 0 or 1− Willing to consent to tumor biopsies− Adequate renal, hepatic and bone marrow function− Prothrombin time and activated partial thromboplastin time

within normal rangeKey Exclusion Criteria

− Known history or evidence of significant immunodeficiency− Administration of an investigational drug in the 28 days, or six

half-lives (whichever is longer) before the first dose of studytreatment

− Major surgery or treatment with any chemotherapy, radiationtherapy, biologics for cancer or investigational therapy in the 28days before the first dose of study treatment

− Symptomatic brain metastases or any leptomeningealmetastasis that is symptomatic and/or requires treatment

− Any history of renal disease or renal injury or autoimmunedisease

− History of coagulopathy, transient ischaemic attacks,cerebrovascular accidents or venous thromboembolism

− Previous treatment with enadenotucirev or an anti-CD40antibody

− Patients at an increased risk due to tumor flare that may lead tointestinal obstruction, obstruction of the ureter or airway

− Clinically or radiologically suspected, or evidence of,lymphangitic carcinomatosis

Rationale

Figure 2 Proposed Mechanism of Action

• NG-350A is a transgene modified variant of the oncolytic platformvirus enadenotucirev which expresses a fully human agonist anti-cluster of differentiation 40 (anti-CD40) antibody

• The platform virus enadenotucirev is a tumor-selective chimericAd11/Ad3 group B oncolytic adenovirus developed using aprocess of directed evolution1

• Phase I clinical studies of the platform virus have identified a well-tolerated dose and regimen for enadenotucirev monotherapy2

Figure 1 Relative Structures of Ad11, Enadenotucirev and NG-350A

• NG-350A infects and selectively replicates in tumor cells• The advantage of encoding anti-CD40 within an oncolytic virus is

the ability to potentially achieve very high levels within the tumor,with limited systemic exposure, coupled with direct cytotoxicitydue to viral lysis and stimulation of the immune-system

• Anti-CD40 antibodies are expected to activate dendritic cells,macrophages and B-cells to drive CD4 and CD8 T cell immuno-inflammatory responses and immune mediated tumor cell killing

Primary Endpoints− Incidence of adverse events, SAEs, adverse events meeting

protocol-defined DLT criteria, severe adverse events, adverseevents leading to study treatment or study discontinuation, andadverse events resulting in death

Secondary Endpoints− Incidence of safety laboratory assessment abnormalities,

abnormalities in vital signs or other clinical safety assessments− ORR, DCR, median DOR, median PFS and PFS rate at 8, 16 and

24 weeks assessed by RECIST Version 1.1 and iRECIST− Overall survival− Blood concentrations of NG-350A− Anti-NG-350A antibody titres

Exploratory Endpoints− Anti-CD40 antibody titres− Measurement of cytokine levels in blood− Measurement of virus genomes in the tumor− Measurement of virus genomes in buccal mucosa swabs, urine

and stool samples− Summary measures of PSA, CEA, CA 125, CA19-9 (as

appropriate) − Identification of analytical methods for future use

References

Study Status

Patient Eligibility Criteria

Background Study Design

Primary Objectives− To characterise the safety and tolerability of NG-350A in patients

with metastatic or advanced epithelial tumorsSecondary Objectives− To determine the recommended dose of NG-350A for further

development in patients with metastatic or advanced epithelialtumors

− To explore the preliminary anti-tumour activity of NG-350A inpatients with metastatic or advanced epithelial tumours usingResponse Evaluation Criteria in Solid Tumors (RECIST) Version 1.1and immune Response Evaluation Criteria in Solid Tumours(iRECIST)

− To assess the pharmacokinetics and immunogenicity of NG-350AExploratory Objectives

− To generate data supporting immunological mechanism of actionof NG-350A

Study Objectives

Study Outcome Measures