Randomized placebo-controlled Phase 1 trial in healthy volunteers investigating safety, PK and PD of exoIL-12-a novel engineered exosome therapeutic candidate

Abstract

Background: Interleukin-12 is an active cytokine for cancer treatment, however the full potential has yet to be realized despite extensive exploration of dose, schedule, and route and method of administration. These approaches have been limited by systemic exposure, resulting in serious adverse events (SAEs) and/or unpredictable pharmacology. exoIL-12™ is a novel, engineered-exosome that displays functional IL-12 on the surface and is designed for local intra-tumoral administration and retention. Objectives of the study: A Phase 1 study in two parts is being conducted. Part A was a randomized placebo-controlled, single ascending dose trial in healthy volunteers to investigate safety, tolerability and both local and systemic pharmacokinetics (PK) and pharmacodynamics (PD). Methodology: A total of 25 male subjects across 5 cohorts were enrolled and randomized 3:2 to exoIL-12 vs placebo. Study drug was administered subcutaneously to each of the 5 cohorts at dose levels of exoIL-12 of 0.3, 1.0, 3.0, 6.0 and 12.0 µg, respectively. Study subjects were admitted to a Phase 1 unit on day -1 and discharged on day 2 and followed for safety and tolerability until day 29. PK and PD assessments included IL-12, IFNγ and IP-10 levels in plasma and IL-12 and IP-10 in serial skin punch biopsies surrounding the injection site. Results: No SAEs were observed. Only mild AEs were recorded. of the AEs were considered related to the study drug. exoIL-12 demonstrated no systemic IL-12 exposure. All blood samples showed IL-12 levels below the limit of quantification (8 pg/mL) at all dose levels. Confirmation of local retention of IL-12 will be assessed by measurement of IL-12 levels in skin punch biopsies pre-treatment and at 24 hrs, day 8 and day 15 post treatment. Systemic and local pharmacodynamic effects will be assessed by quantifying IP-10 levels in serial blood samples and skin punch biopsies. Conclusions: Studies of recombinant IL-12 conducted by others in healthy volunteers at comparable dose levels to the present study resulted in dose dependent systemic IL-12 exposure as well as IFNγ and IP-10 production and common adverse events such as fever, chills, myalgia, headache, and muscle pain. In contrast, exoIL-12 demonstrated a favorable safety and tolerability profile with no treatment-related adverse events and no systemic IL-12 exposure. Local IL-12 levels in the skin as well as pharmacodynamic data from blood and skin samples will be presented. The study is advancing into Part B, an open label study of exoIL-12 in patients with cutaneous T-cell lymphoma.