Abstract 1075TiP
Background
Interleukin 12 (IL-12) is a central mediator of TH1 immune response, releasing interferon-γ (IFNγ) from activated natural killer (NK), NKT and T cells to drive antitumor activity. A TH1 polarized tumor microenvironment (TME) with high IFNγ and PD-L1 may favor response to PD-1/PD-L1 blockade. However, systemic recombinant IL-12 is poorly tolerated. MEDI1191 is an IL-12 mRNA-based therapy for IT injection, designed to increase local IL-12 expression and enhance T cell response with less systemic toxicity. In mouse models, IT IL-12 mRNA shrinks tumors and confers protective immunity. Combination with PD-L1 blockade enhances cytotoxic T cell infiltration, efficacy and immunity. MEDI1191 induces IL-12 expression in patient-derived xenograft models and leads to TH1 TME transformation in ex vivo samples, suggesting potential clinical utility.
Trial design
This phase I, multicenter, open-label, dose-escalation (Part 1) and expansion (Part 2) study (NCT03946800) evaluates the safety and efficacy of MEDI1191 IT in sequential or concurrent combination with durvalumab 1500 mg Q4W IV. Treatment continues for ≤2 years or until progression or unacceptable toxicity. Part 2 will enrol patients with immunotherapy-pretreated NSCLC and uses concurrent dosing in superficial and deep-seated lesions. Eligible patients are >18 years old with ECOG PS 0/1, and histologic or cytologic confirmation of advanced solid tumors. They must have ≥1 superficial lesion or ≥2 deep-seated lesions suitable for IT dosing, and ≥1 noninjected lesion measurable by RECIST v1.1. They must have had ≥1 prior line of standard systemic therapy for R/M disease. Patients with prior IL-12 treatment are excluded. Primary endpoints for Part 1 are safety, tolerability and dose-limiting toxicities to identify the maximum tolerated dose (sequential and concurrent). The primary endpoint in Part 2 is objective response rate. Secondary endpoints include safety for Part 2 and efficacy (disease control rate, duration of response, time to response, anenestic effect, PFS and OS), pharmacokinetics and immunogenicity for both Parts. Planned enrolment is up to 220 patients at 12 sites in the US, Spain, France and the Netherlands. Recruitment began May 15, 2019.
Clinical trial identification
NCT03946800.
Editorial acknowledgement
Medical writing support wasprovided by Daisy Byeof Cirrus Communications, an Ashfield company, and was funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
T. Marron: Honoraria (self), Speaker Bureau/Expert testimony, Fees associated with running trial; expert tumor board, reimbursement was less than 10,000USD: AstraZeneca. V. Subbiah: Advisory/Consultancy, Research grant/Funding (institution): Loxo Oncology/Eli Lilly; Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Nanocarrier; Research grant/Funding (institution): Vegenics; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Northwest Biotherapeutics; Research grant/Funding (institution): Berghealth; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Incyte; Research grant/Funding (institution): Fujifilm; Research grant/Funding (institution), Travel/Accommodation/Expenses: PharmaMar; Research grant/Funding (institution): D3; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Multivir; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Alfasigma; Research grant/Funding (institution): Agensys; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): Idera Pharma; Research grant/Funding (institution): InhibRx; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Blueprint Medicines; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Altum; Research grant/Funding (institution): Dragonfly Therapeutics; Research grant/Funding (institution): Takeda; Speaker Bureau/Expert testimony, Research grant/Funding (institution): National Comprehensive Cancer Network; Research grant/Funding (institution): NCI-CTEP and UT MD Anderson Cancer Center; Research grant/Funding (institution): Turning Point Therapeutics; Research grant/Funding (institution): Boston Pharmaceuticals; Advisory/Consultancy, Travel/Accommodation/Expenses: Helsinn; Advisory/Consultancy: R-Pharm US; Advisory/Consultancy: QED Pharma; Travel/Accommodation/Expenses: ASCO; Travel/Accommodation/Expenses: ESMO; Honoraria (self), Other: Medscape. O. Hamid: Research grant/Funding (institution): Arcus; Advisory/Consultancy, Research grant/Funding (institution): Aduro; Advisory/Consultancy, Research grant/Funding (institution): Akeso; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Array; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): CytomX; Research grant/Funding (institution): Exelixis; Advisory/Consultancy, Research grant/Funding (institution): Roche/Genentech; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution): Immunocore; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Iovance; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/Funding (institution): Nextcure; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Sanofi Regeneron; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy, Research grant/Funding (institution): Zelluna; Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Janssen; Advisory/Consultancy: Tempus. M. Hellmann: Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self), Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution): Roche/Genentech; Honoraria (self): Janssen; Honoraria (self): Nektar; Honoraria (self): Syndax; Honoraria (self): Mirati; Honoraria (self): Shattuck Labs; Licensing/Royalties, Patent filed by MSK related to use of tmb to predict response to immunotherapy: MSK-PGDx. B.A. Carneiro: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Astellas. S.P. Patel: Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Illumina; Advisory/Consultancy, Research grant/Funding (institution): Nektar; Advisory/Consultancy, Research grant/Funding (institution): Tempus; Research grant/Funding (institution): Eli Lilly; Research grant/Funding (institution): Fate Therapeutics; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche/Genentech; Research grant/Funding (institution): Xcovery; Research grant/Funding (institution): Genocea; Research grant/Funding (institution): Iovance. E. de Vries: Advisory/Consultancy: NSABP Foundation; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Chugai; Research grant/Funding (institution): Cytomx; Research grant/Funding (institution): Nordix Nanovector; Research grant/Funding (institution): G1 Therapeutics; Research grant/Funding (institution): Radius Health; Research grant/Funding (institution): Bayer; Advisory/Consultancy: Synthon; Research grant/Funding (institution): Servier; Research grant/Funding (institution): Regeneron. N. Luheshi, O. Hamid, A. Gascó Hernández: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.