(P 111) INTERIM ANALYSIS OF A PHASE 1 STUDY USING IL12-FHAB WITH OPTIMIZED PHARMACOKINETICS

Objective: Recombinant interleukins (IL) have had limited clinical success due to inefficient tumor targeting and short pharmacokinetics (PK), requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 is a promising cancer treatment due to its activation of T and natural killer (NK) lymphocytes to produce interferon-gamma (IFN-γ), yet dosing strategies have failed to provide adequate therapeutic benefit in humans. To address these issues, we developed a novel platform that delivers either mono- or bifunctional immunomodulator(s) linked to a Fully-Human, Albumin Binding scFv domain (FHAB®). The platform provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC, which results in an improved PK profile, in addition to a dose-sparing effect that decreases the toxicity risk, and provides a broader therapeutic index. Excellent tumor growth inhibition was seen using a “cold” immunosuppressive B16F10 melanoma model for comparing the efficacy of IL12-FHAB with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells.

Methods: We are conducting a first-in-human, dose-escalation trial, SB101, to evaluate the safety and tolerability of SON 1010 (IL12-FHAB) and to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors (NCT05352750). The study has a traditional 3+3 design, modified to take advantage of the known tachyphylaxis of IL-12 with the introduction of a desensitizing first dose to allow administration of higher maintenance doses.

Results: No dose-limiting toxicities have been encountered in the first 3 dose cohorts and the MTD is at least 300 ng/kg. While some adverse events are similar to those reported in other studies of IL 12 at these doses, they have been transient and tolerable, allowing further dose escalation. Increases in IFN-γ were dose-related, controlled, and prolonged. The levels peaked at 24 to 48 hours and returned to baseline after 2 to 4 weeks. Low levels of IL-10 were induced in a dose-dependent manner. No drug-related increase was seen with IL-1β, IL-6, IL-8, or TNF-α and there has been no evidence of cytokine release syndrome. The preliminary geomean elimination half-life (T½) was 113 hours with single-compartment kinetics, compared with 12 hrs for SC rhIL-12. Interestingly, two-compartment kinetics were seen in a parallel single-ascending dose (SAD) study of SON-1010 in healthy volunteers. The accumulation estimates are within the margin of error and are not likely to be physiologically significant with subcutaneous dosing of SON-1010 every 3 weeks. Nine of 15 patients had stable disease at the first follow-up CT, 4 of whom were progressing at study entry. Five patients were stable at 4 months (36% clinical benefit) and 2 had unconfirmed progressive disease; 1 patient remains stable after 12 months on SON-1010 with evidence of tumor regression.

Conclusion: SON-1010 has been tolerated well with a delayed PK profile and causes a controlled and prolonged elevation of IFN-γ. The PK comparison with dosing in healthy volunteers suggests that SON-1010 is being retained in tumor tissue, as the FHAB platform was designed to do. This monofunctional immunotherapeutic drug candidate may have a positive synergistic effect with an immune checkpoint inhibitor (ICI), particularly with ‘cold’ tumors that over-express SPARC like sarcoma and ovarian cancer. The next stage of development will be to explore the MTD of SON-1010 in combination with an ICI, then to compare that approach with the standard of care in Phase 2.