Abstract LB432: Clinical-stage anticancer agent BOLD-100 demonstrates protective effects against oxaliplatin-induced peripheral neuropathy in an in-vivo rat model

Abstract BOLD-100 is a first-in-class, ruthenium-based anticancer agent in Phase 2 clinical development for advanced gastrointestinal (GI) cancers in combination with FOLFOX. Clinical results have shown that BOLD-100 combined with FOLFOX improves overall survival (OS) and progression-free survival (PFS) in patients with advanced colon, gastric, and bile duct cancers. Emerging clinical evidence indicates a very well tolerated safety profile for BOLD-100 in combination with FOLFOX. While FOLFOX is a first- or second-line standard-of-care therapy for GI cancers, its clinical utility is limited by the induction of acute and chronic peripheral neuropathies. Notably, in clinical trial BOLD-100-001 (NCT04421820), an unexpected reduction in oxaliplatin-induced peripheral neuropathy (OIPN) was observed. In patients treated with BOLD-100 and FOLFOX, any-grade neuropathy was reduced compared to benchmark FOLFOX-alone patients: mCRC (14% vs. 53%), BTC (36% vs. 67%), and GC (19% vs. 63%). However, translational and preclinical investigations into the neuroprotective effects of BOLD-100 are necessary. To assess BOLD-100’s neuroprotective effects in an in-vivo model, Sprague-Dawley (SD) rats received intraperitoneal low-dose oxaliplatin (0.5 mg/kg) or high-dose oxaliplatin (1.5 mg/kg) twice weekly until Day 17. Concurrently, BOLD-100 (40 mg/kg) or vehicle (10 mL/kg) was administered via slow IV bolus (∼30 seconds) twice weekly. Cold allodynia was measured using the acetone spray test at baseline (Day -1) and 0.5 hours post-oxaliplatin administration on each dosing day. Rats treated only with oxaliplatin developed significant cold allodynia by Day 7 (high dose) and Day 10 (low dose), whereas animals co-treated with BOLD-100 substantially prevented the development of peripheral neuropathy at both oxaliplatin doses. In the high-dose model, significant attenuation of OIPN was observed as early as Day 7 (p = 0.02), with highly significant reductions from Day 10 (p = 0.0009) to Day 21 (p < 0.000001). In the low-dose model, a complete attenuation of OIPN was observed from Day 10 (p = 0.01) to Day 21 (p = 0.00007). To elucidate possible mechanisms, we used plasma samples from patients in clinical trial BOLD-100-001, we observed a strong induction of multiple cytokines relevant to neuroprotective effects. Importantly, patients who developed neurotoxicity-related adverse events during the study appeared to have a reduced capacity to induce these cytokines after BOLD-100 treatment. Collectively, these findings provide strong evidence that BOLD-100 not only enhances oxaliplatin-based therapy in GI malignancies but also improves its clinical utility by markedly reducing OIPN. Ongoing clinical studies are evaluating BOLD-100’s neuroprotective benefits and its potential to enhance the therapeutic index of standard-of-care regimens for advanced GI cancers. Citation Format: Ashish Kumar, Brian Park, Malcolm Snow, Russell McAllister, Jim Pankovich, Mark Bazett. Clinical-stage anticancer agent BOLD-100 demonstrates protective effects against oxaliplatin-induced peripheral neuropathy in an in-vivo rat model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB432.