Trial in Progress: ST-067 (decoy-resistant IL-18) with Teclistamab in Multiple Myeloma

Background: Teclistamab (tec) is a bispecific antibody (bsAb) which binds BCMA on multiple myeloma (MM) cells and CD3 on T-cells, leading to tumor cell death. Tec is currently approved for relapsed/refractory (R/R) MM based on the MajesTEC-1 trial, which demonstrated an ORR of 63% with median progression-free survival (PFS) of 11.3 months. However, PFS is typically shorter in the real-world setting (Dima et al, TCT 2024, Mohan et al, BCJ 2024). Interleukin 18 (IL-18) is an immunostimulatory cytokine that triggers T-cell proliferation and differentiation into the Th1 phenotype important in anticancer immunity. Recently published work suggests that IL-18-armored CAR T-cells targeting BCMA (but not unarmored cells without paracrine IL-18 secretion) can eliminate myeloma cells even with low BCMA expression (Ng et al, Blood 2024). Trials of recombinant IL-18 in oncology have been disappointing due to its inhibition by IL-18 binding protein, a high-affinity decoy receptor that acts as a cytokine sink. ST-067 is a decoy-resistant IL-18 variant shown to potentiate T-cell activity in pre-clinical models (Minnie et al, Sci Immunol 2022).

Given the room for improvement with responses to bsAb therapy in patients with MM, we are conducting a Phase 1b study to investigate the combination of tec and ST-067 in MM after a ST-067 lead-in. The ST-067 monotherapy lead-in allows for safety evaluation as well as potential T-cell ‘priming’ before tec initiation, while then continuing ST-067 in combination with tec may allow for deeper and more durable responses in MM as compared to tec alone.

Methods: This is an open-label single-arm Phase 1b trial of ST-067, a decoy-receptor resistant version of IL-18, in R/R MM. Patients will receive ST-067 monotherapy during Cycle 1 (28 days) and then tec + ST-067 from Cycle 2 onwards. Enrollment of 20 patients is planned. Eligibility criteria include MM with measurable disease, eligibility to receive commercial tec (≥4 prior lines, including exposure to a PI, IMID, and CD38 mAb), age ≥18, ECOG PS 0-2, and adequate organ function. Patients with ≥12 months since prior BCMA therapy are also eligible.

During Cycle 1, participants will receive ST-067 monotherapy (subcutaneously once per week) at escalating dose levels (DL): DL1 0.03 milligrams per kilogram (mg/kg), DL2 0.06 mg/kg, and DL3 0.12 mg/kg. Patients will be hospitalized for their first dose to evaluate for CRS. During Cycle 2, ST-067 will be administered with full-dose tec following inpatient tec step-up dosing. Doses of ST-067 and tec must be separated ≥48 hours and any CRS must have resolved before administration of the next agent. From Cycle 3 onward, ST-067 will be dosed q2week subcutaneously while tec will be dosed every 1-2 weeks per investigator discretion. For patients who have achieved ≥PR by IMWG criteria and received at least 3 treatment-level tec doses, ST-067 and tec can be dosed on the same day. The primary endpoint is evaluation of the safety profile and optimal biologic dose of ST-067 as monotherapy and with tec; key DLTs include Grade 3+ CRS and Grade 2+ ICANS. Other endpoints include efficacy (including MRD status at Day +28) and exploratory markers of T-cell fitness and tumor burden. Enrollment is expected to begin in the fall of 2024.

Discussion: ST-067 can potentiate T-cell function, particularly in effector CD8+ T-cells that are critical to tec's anti-MM activity from the very first dose (Firestone et al, Blood Adv 2024). Additionally, ST-067 may be able to promote stem-like memory precursor T-cells that are likely important to long-term responses. If shown to have a favorable safety and efficacy profile in this and future studies, ST-067 has the potential to become a routine addition to bsAb therapy in MM and other malignancies.

Funding: Simcha IL-18, Inc.

Banerjee:Abbvie; JNJ; Novartis; Pack Health; Prothena; Sanofi: Research Funding; Adaptive; BMS; Caribou Biosciences; Genentech; GSK; JNJ / Janssen; Karyopharm; Legend Biotech; Pfizer; Sanofi; SparkCures: Consultancy. Barton:Simcha IL-18, Inc.: Current Employment. Mangone:Simcha IL-18, Inc.: Current Employment. McQueen:Simcha IL-18, Inc.: Current Employment. Gauthier:Sobi, Juno Therapeutics, a BMS company, Celgene, and Angiocrine Bioscience: Research Funding; Sobi, Legend Biotech, Janssen, Kite Pharma, a Gilead company, and MorphoSys: Consultancy. Ring:Simcha Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Gopal:Merck: Consultancy, Honoraria, Research Funding; I-Mab bio: Research Funding; IgM Bio: Research Funding; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; SeaGen: Research Funding; Teva: Research Funding; Genmab: Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys/Incyte: Consultancy, Honoraria; ADCT: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Compliment: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; Fresenius-Kabi: Consultancy, Honoraria; Scitek: Consultancy, Honoraria; Sana: Consultancy, Honoraria. Hill:Compass Therapeutics, Syndax Pharmaceuticals, Applied Mo- lecular Transport, Serplus Technology, Heat Biologics, Laevoroc Oncology, iTeos Therapeutics, Genentech, and CSL Behring.: Research Funding; Commonwealth Serum Laboratories (CSL): Consultancy; Neoleukin Therapeutics: Consultancy; Generon Corporation, NapaJen Pharma, iTeos Ther- apeutics, and Neoleukin Therapeutics: Consultancy; Cynata Therapeutics: Consultancy; NapaJen Pharma: Consultancy; CSL Behring: Consultancy; iTeos Therapeutics: Consultancy. Cowan:HopeAI: Consultancy, Current holder of stock options in a privately-held company; Juno/Celgene: Research Funding; Abbvie: Research Funding; Caelum: Research Funding; Harpoon: Research Funding; Nektar: Research Funding; Regeneron: Research Funding; IgM biosciences: Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sebia: Consultancy.