First-in-human clinical evaluation of ST-01156, an optimized and selective degrader of RNA-binding motif 39 (RBM39): A phase 1 study in advanced solid malignancies with a focus on RBM39-dependent cancers.

TPS3164 Background: ST-01156 is an orally administered agent developed to degrade RBM39, a protein target that is principally involved with splicing RNA into messenger RNA and is commonly upregulated in cancer. ST-01156 has entered phase 1 clinical trials for the treatment of several cancer types supported by its novel mechanism of action and data from preclinical testing. The lead optimization process for ST-01156 maximized degradation selectivity, anticancer potency, metabolic stability (including deuteration), and other drug-like properties. The ability of ST-01156 to achieve functionally meaningful and selective effects is exemplified by complete degradation of RBM39 within hours following treatment in vitro, accompanied by downstream mis-splicing of pathogenic transcripts, most notably the EWSR1-FLl1 fusion transcript driving Ewing sarcoma (ES). Adding to this effect, ST-01156 depleted proteins involved in DNA damage repair (DDR), supporting the potential for synthetic lethality with cancer cells that depend on proficient DDR. RBM39 is also involved in the splicing of KRAS isoforms thought to be essential for the proliferation and survival of oncogenic KRAS cancer stem cells, providing an anticancer mechanism distinct from the mechanisms of current KRAS inhibitory agents. In advanced hepatocellular carcinoma (aHCC), RBM39 is substantially overexpressed and likely impedes essential arginine sensor activities. In addition to demonstrating robust activity in these malignancies, ST-01156 is highly active in patient-derived xenograft models of neuroblastoma, biliary tract carcinoma (BTC), and endometrial carcinoma (EC). In animal toxicology studies, hematologic and gastrointestinal tissues were most susceptible to RBM39 inhibition. Methods: In the first-in-human study, ST-01156 doses will be adaptively escalated based on the rate and severity of adverse events in trial participants with advanced solid malignancies. ST-01156 will be administered orally for 5 consecutive days every 7 days with an option of adapting a continuous dosing schedule, if tolerable. Backfilling of safe dose levels with participants with high priority malignancies will be allowed. In addition to traditional safety and tolerability endpoints, dose escalation and Phase 2 dose derivation will be based on pharmacokinetic (PK) endpoints and real-time RBM39 targeting measurements in peripheral mononuclear cells. The optimal dose of ST-01156 derived from safety tolerability, PK and pharmacodynamic data will be evaluated in trial participants in the following expansion cohorts: A, ES; B, aHCC; C, KRAS -mutant cancers; and D, an adaptive cohort of cancers projected to be susceptible to RBM39 inhibition including BTC, EC, and cancers with DDR aberrations. Clinical trial information: NCT07197554 .