Bxq-350 in combination with FOLFOX7 and bevacizumab: Evaluation of effect on oxaliplatin-induced CIPN—A phase 1b/2 trial to assess the efficacy and safety of BXQ-350, a first-in-class sphingolipid metabolism modulator, in newly diagnosed metastatic colorectal carcinoma.

105Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect associated with many cancer drugs and is highly prevalent in mCRC patients receiving oxaliplatin-based regimens. CIPN can severely impact quality of life (QoL) and may require dose vacation, reduction or interruption. CIPN pathology is complex and not completely understood; preclinical and clinical data have shown inflammatory (IL-6, Il-8, IL-10) and immune involvement as well as elevated levels of sphingolipids, a class of bioactive signaling molecules. BXQ-350 is a nanovesicle formulation of Saposin C, an allosteric activator of sphingolipid metabolism that normalizes dysregulated sphingolipid metabolism by lowering S1P, GM3 and GluCer levels while it increases ceramide level, promoting a return to homeostasis. In a single agent Phase 1 study, BXQ-350 was safe and well-tolerated and showed signs of activity. Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 is still on study after 7 years. One patient self-reported an improvement of their pre-existing CIPN symptoms after BXQ-350 administration; this observation was confirmed in 4 of 10 patients with established CIPN at the time of enrollment. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab (SoC) in newly diagnosed mCRC patients (NCT05322590). Primary objectives are to assess safety and preliminary efficacy of this combination, and to determine cumulative oxaliplatin dose. Secondary objectives include intensity, frequency and time to onset of CIPN. Results: The Phase Ib trial enrolled 33 oxaliplatin dosing evaluable patients; all patients completed the primary treatment period (6 months of SoC treatment plus BXQ-350). Amongst the 33 patients, 19 completed the full 12 Cycles of oxaliplatin dosing, 28 completed at least 8 Cycles with only 2 patients having dosing halted before Cycle 8 due to CIPN. There were no reported Grade 4 and only 3 reported Grade 3 CIPN AEs, all occurred after Cycle 12. Analysis of Neurofibrillary Light Chain (NfL) biomarkers suggests concordance with physician and patient reported outcomes. Conclusions: Results show that BXQ-350 was safe and well tolerated in the combination. Data suggest that BXQ-350 may provide additional clinical benefits and may reduce intensity or delay onset of CIPN, allowing for increased cumulative dosing of oxaliplatin and relative dose intensity in 1L mCRC. Clinical trial information: NCT05322590.