IL-12 is a strong driver of a TH1 immune response, but systemic recombinant IL-12 is poorly tolerated clinically. MEDI1191 (IL-12 mRNA) is a lipid nanoparticle (LNP)-formulated therapy developed for intratumoral (IT) injection, designed to drive local IL-12 production and induce anenestic anti-tumor activity. In preclinical models, IT IL-12 mRNA induces a potent TH1-mediated antitumor response, that is further enhanced by PD-L1 blockade.
This phase I, multicenter, open-label, dose-escalation (part 1) and expansion (part 2) study evaluates the safety and efficacy of MEDI1191 IT in sequential or concurrent combination with durvalumab 1500 mg Q4W IV in advanced solid tumors with superficial and deep-seated lesions. Patients (pts) who have progressed on at least 1 line of standard systemic therapy were eligible, including IO naïve or pre-treated pts. Primary endpoints for part 1 are safety and to identify the maximum tolerated dose and a pharmacodynamic active dose. Secondary endpoints for part 1 include efficacy (disease control rate, duration of response, time to response, PFS, and OS), pharmacokinetics and immunogenicity. Here we will be presenting preliminary data that needs further validation.
From May 2019 to December 2020, 10 pts were enrolled across three dose escalation cohorts in part 1 in pts with superficial lesions. 6 out of 10 were IO-pretreated pts. No DLT, AESI, ≥ G3 TRAE or TR-SAE were reported. To date, two partial responses have been observed, both pts had received IO therapies and had PD-L1 negative tumors, including one pt with melanoma with tumor shrinkage of both injected and non-injected lesions following 2 doses of MEDI1191 and prior to durvalumab. Preliminary pharmacodynamic analysis indicate that MEDI1191 induced transient elevation in serum levels of IL-12; and concordant changes in IFN-g and CXCL10.
Sequential combination of IT MEDI119 with IV durvalumab was well tolerated and showed encouraging preliminary antitumor and pharmacodynamic activity including in IO pre-treated pts, consistent with the expected mechanism of action. The study is active and recruiting.
NCT03946800.
AstraZeneca.
AstraZeneca.
O. Hamid: Research grant/Funding (self): Moderna. M. Hellman: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca. B. Carneiro, V. Subbiah: Research grant/Funding (self): AstraZeneca. T. Marron: Advisory/Consultancy: AstraZeneca. J. Eyles, V. Dubois, B. Ridgway, O. Hamid, A. Gasco Hernandez: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.