Neuroprotective potential of BOLD-100 when utilized in combination with FOLFOX for the treatment of advanced gastrointestinal cancers.

Abstract

e15029 Background: BOLD-100 is a ruthenium-based anticancer agent in Phase 2 development for gastrointestinal (GI) cancers (NCT04421820). Previous data showed BOLD-100 plus FOLFOX improved overall survival (OS) and progression-free survival (PFS) in patients (pts) with advanced colorectal (mCRC), gastric (GC), and biliary tract cancer (BTC). Pts treated with the BOLD-100 combination had a lower incidence of oxaliplatin-induced peripheral neuropathy (OIPN). Many pts treated with FOLFOX experience OIPN leading to dose reductions and treatment discontinuations. A retrospective analysis of adverse events (AEs) from this study was conducted to investigate the impact of BOLD-100 on OIPN. Methods: BOLD-100-001 is a prospective, open-label, phase 2 study in pts with mCRC, GC, BTC & pancreatic cancer with measurable disease (RECIST v1.1) and BRAF wildtype tumor status. Pts received FOLFOX plus BOLD-100 every 2 weeks via IV infusion. OIPN-related AEs were analyzed and compared to historical benchmarks. Analyses included OIPN incidence by BOLD-100 dose level, demographics, and oxaliplatin treatment delays or discontinuations. Univariate and multivariate analyses were performed. Results: Study enrolled 109 participants. Median age was 62 years (range 48-84). Female pts made up 45%, all pts had an ECOG PS ≤1. All pts had a primary diagnosis of adenocarcinoma, 42 (39%) colorectal, 22 (20%) bile duct, 24 (22%) pancreatic, and 21 (19%) gastric cancer. 106 pts (97%) were stage IV at study entry and all but one had prior chemotherapy in the advanced setting. The median number of prior systemic therapies was 3 (range 0-8) with 95% treated with oxaliplatin (65%) or cisplatin (30%). 45 pts (41%) had prior neuropathy. On study, 24 pts (22%) had at least one OIPN-associated AE. Lower PN incidence was observed across all cohorts relative to benchmarks: mCRC (14% vs 53%), BTC (36% vs 68%), GC (19% vs 63%), and pancreatic cancer (29% vs 38%). Only 9 pts (8.2%) discontinued oxaliplatin, with only 2 attributed to OIPN. Of 69 dose reductions, 16 (23%) were due to OIPN. Pts at the highest BOLD-100 dose level (625 mg/m 2 ) had the lowest OIPN incidence. Multivariate analysis suggests Asian descent (OR = 0.09; p = 0.04) and medical history of prior neuropathy (OR = 0.18; p = 0.02) were significantly associated with the absence of OIPN. Univariate analysis suggested longer OS (OR = 1.1; p = 0.006), PFS (OR = 1.13; p = 0.002), and a higher number of cycles (OR = 1.17; p = 0.0003) were associated with an increased likelihood of OIPN. Conclusions: Analysis of safety and dosing data from BOLD-100-001 suggests a potential neuroprotective effect of BOLD-100 against FOLFOX-induced PN. Further investigations are ongoing to characterize this effect in a randomized arm of the BOLD-100-001 clinical trial which is exploring changes in health-related and neuropathy-related quality of life per EORTC-QLQ-30 and EORTC-QLQ-CIPN20 scores. Clinical trial information: NCT04421820 .