The Immunocytokine M9241 in the Treatment of Prostate Cancer (pca): Clinical and Immune Data from a Phase 1 Study.

127 Background: Interleukin-12 (IL-12) is a proinflammatory cytokine that plays a critical role in regulating the transition from innate to adaptive immunity but has toxicity with systemic administration. M9241 is an immunocytokine composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single and double stranded DNA. Thus, M9241 targets delivery to regions of tumor necrosis where DNA has become exposed. NCT01417546, a phase I trial of M9241 at escalating doses, established safety and dosing (Strauss J et al, CCR 2019). This was the first use of M9241 in human subjects with solid tumors including PCa. Methods: Nine patients (pts) with PCa enrolled in the phase 1 study, not all of which were presented previously. M9241 was given subcutaneously every 4 weeks (0.1-21.8mcg/kg) or every 2 weeks (12-16.8mcg/kg). PSA declines and immune responses were evaluated including systemic cytokine levels and 30 markers on 158 circulating immune cell subsets. Results: Nine PCa pts were treated with NHS-IL12 and 8 were evaluable for response, including 6 pts with biochemical recurrence and 2 with metastatic castration resistant prostate cancer (one patient discontinued the study treatment after 1 dose due to grade 3 elevation in ALT). There were no adverse events (AEs) of grade >4. Additional grade 3 toxicities included one each of: leukopenia, neutropenia and lymphopenia. The most common AEs of any grade were lymphopenia (77.8%), fatigue (55.6%), and ALT elevation (55.6%). 5 of 8 (62.5%) had PSA declines ranging from 8-42%. After treatment with M9241, evaluable pts had increases in systemic IL-10, TNF and INFg. Additional immune changes included increases in activated subpopulation of natural killer (NK) cells, consistent with the phase 1 experience. Conclusions: M9241 was found to be safe and well tolerated in PCa pts. PSA declines occurred in 5 of 8 evaluable pts. As with the phase 1 study, increases in NK subpopulations were seen in the small number of evaluable pts. These preliminary findings of a necrosis-targeting immunocytokine will be evaluated further in combination studies with cytotoxic therapy. M9241 is currently being evaluated in combination with docetaxel in metastatic prostate cancer (NCT04633252). Clinical trial information: NCT01417546.