![]() Despite large acute increases in specific cytokines, no changes to baseline levels over multiple treatment cycles were observed. IL-10, a cytokine previously investigated as an anticancer therapeutic, increased significantly by 1 hour (6.7X increase) and by 6 hours (84.5X increase) after treatment, before reverting to baseline levels by 48 hours. Multiple cytokines showed short-term (1 to 48 hours) transient increases in plasma concentration levels, including IL-10, IL-27, G-CSF, MIP-1β, IP-10, IL-2, IL-18 and TNFα. In 326 samples collected from 15 patients, 48 cytokines were measured via multiplex. To investigate the pharmacodynamics of immune markers, plasma samples were collected at baseline and 1, 6, 24, and 48 hours after initiation of BOLD-100 plus FOLFOX treatment for each of the first 4 cycles, and then at baseline for all subsequent cycles. In this Phase 1b study, BOLD-100 was administered via IV infusion for 60-90 minutes immediately prior to FOLFOX on a 2-week cycle. A recently completed Phase 1b trial investigating BOLD-100 in combination with FOLFOX demonstrated a 3X improvement in progression-free survival (PFS) in 3rd line or later metastatic colorectal cancer patients compared to existing therapies, with a favorable safety profile. BOLD-100 can also alter immune responses, including through induction of immunogenic cell death, but these responses have not been investigated in a clinical population. Collectively, these pathways result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies. BOLD-100, currently in a multinational Phase 2 trial, is a first-in-class metallotherapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition, and (2) induces reactive oxygen species (ROS), leading to DNA damage and cell cycle arrest. These immune responses can drive efficacy in specific patient populations and/or in combination with other oncology drugs. Proven metallotherapeutics, such as cisplatin and oxaliplatin, alter immune responses as part of their multimodal mechanisms-of-action.
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