A Phase 1b/2a study to evaluate the efficacy and safety of BXQ-350 in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal carcinoma patients (mCRC): Evidence of lower incidence and severity of CIPN events

Background: Dysregulated sphingolipid metabolism is common to many cancer types, including mCRC, and leads to elevated concentrations of gangliosides (GM3), lactosylceramides (LacCer), glucosylceramides (GluCer) and sphingosine-1-phosphate (S1P) and lower concentration of ceramides (Cer). In mCRC patients, several studies have shown elevated concentrations of these sphingolipids are associated with worse prognosis and poor survival. Therefore, targeting dysregulated sphingolipid metabolism and returning sphingolipid metabolism to homeostasis could be a promising therapeutic approach. 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 and immune involvement as well as elevated levels of sphingolipids also involved in cancer progression. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that affects dysregulated sphingolipid metabolism. BXQ-350 lowers GM3, GluCer and S1P levels while it also increases ceramide levels promoting a return to homeostasis. In a single agent Phase 1 study, BXQ-350 was safe and well-tolerated (no DLT, no MTD) and showed signs of activity. Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years. Furthermore, 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. Method: BXQ-350 is being investigated in a Phase 1b/2a study in combination with mFOLFOX7 and Bevacizumab (SoC) in newly diagnosed mCRC patients (NCT05322590). The Phase 1b/2a is a safety dose escalation part to establish the RP2D exploring 1.8 and 2.4 mg/kg BXQ-350 in combination with SoC. Primary objectives are to assess safety and preliminary efficacy of BXQ-350 in this combination. Secondary objectives include longitudinal analysis of several biomarkers, including sphingolipid profiling. Results: A total of 32 evaluable patients were enrolled, and all 32 patients have completed SoC treatment schedule plus BXQ-350. Amongst these 32 patients, 21(66%) are alive and in active follow-up. The disease control rate was 91% (30 pts had SD, PR or CR). As of September 2025, ORR is 61% and median PFS is 10.6 months. Furthermore, 19 (58%) completed the full 12 Cycles of oxaliplatin dosing, 28 (85%) 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. Conclusions: BXQ-350 is safe and well tolerated in the combination. Efficacy and CIPN results suggest that BXQ-350 may provide clinical benefits in combination with FOLFOX7+Bev and reduce, at the same time, incidence and severity of CIPN adverse events allowing for a higher cumulative dose of oxaliplatin