An open-label, multi-center Phase 2 study to assess the safety and efficacy of burixafor (GPC-100) and propranolol with G-CSF for the mobilization of hematopoietic progenitor cells in patients with multiple myeloma

Abstract Background and Significance Autologous hematopoietic cell transplant (AHCT) is standard of care for multiple myeloma (MM) treatment, following induction therapy. Adequate mobilization and number of infused hematopoietic progenitor cells (HPCs) is associated with engraftment and survival outcomes. The increased use of anti-CD38 monoclonal antibodies have been associated with poor HPC mobilization. However, the currently available CXCR4 inhibitors have not been prospectively studied in the era of anti-CD38 antibodies. Burixafor (GPC-100) is a potent and selective small molecule antagonist of CXCR4 that was demonstrated in previous clinical trials to be safe and effective as an HPC mobilization agent alone or in combination with G-CSF. Faster kinetics of mobilization allows the administration of Burixafor on the same day of leukapheresis, compared to the currently FDA approved CXCR4 inhibitors, potentially minimizing healthcare resource utilization and improving patient experience. Propranolol has been clinically shown to inhibit molecular risk markers in MM patients receiving AHCT and have been shown to improve bone marrow cellularity and reduce pro-tumorigenicity. The aim of this study is to boost the bone marrow HPC niche and optimize mobilization in patients with MM eligible for AHCT. Study Design and Methods This study (NCT05561751) is a U.S. only, open-label, multi-site Phase 2 trial. Up to 20 participants were enrolled across 10 sites. The primary objective is to determine the proportion of patients achieving ≥2x106 CD34+ cells/kg in 2 leukapheresis sessions. The study employed a Bayesian Optimal Phase 2 design to characterize the safety and clinical activity of burixafor. Participants self-administered 30 mg propranolol orally twice daily on Days 1-8 and received 10 µg/kg/day G-CSF subcutaneously on Days 3-7. On days 7 and 8, participants received 3.14 mg/kg burixafor intravenously 45 minutes before leukapheresis. Safety monitoring continued up to 28 days post-burixafor for participants who did not proceed to transplant and up to 100 days post-transplant for those who do. Results This interim analysis reports on 10 patients out of 19 enrolled patients who have received at least 1 dose of burixafor. Enrollment has now closed, and the final results of all patients will be disclosed by December 2025. The median age was 63 years (range 42-75) and 60% were male. All patients received lenalidomide-based induction therapy, with 70% also receiving daratumumab. The study met its primary endpoint with all patients successfully collecting ≥2x106 CD34+ cells/kg within two apheresis sessions. Notably, 70% of patients achieved ≥5x106 CD34+ cells/kg within the same timeframe. A total of 277 adverse events (AE) of any grade were reported, 68% of which were transplant-related and 15% deemed related to the study drugs. Of these, 13 AEs were related to GPC-100 observed in 3 patients (30%) that were mostly grade 1 and several that were grade 2 in intensity. Stomach cramps, chest tightness, and flushing occurred concurrently in one patient. Another experienced bone pain deemed related to both GPC-100 and G-CSF, while a third patient had hypokalemia, hypomagnesemia, hypotension, and tachycardia. Notably, no infusion reactions and no diarrhea were observed. AEs related to propranolol included hypotension in 2 patients, grades 1 and 2 respectively. All other AEs related to propranolol were grade 1 or 2, including constipation, fatigue, headache, and hyperglycemia, each observed in 1 patient (10%). AEs related to G-CSF included musculoskeletal pain (40%), headache (20%), anemia (20%), fatigue (10%), hypokalemia (10%), hypomagnesemia (10%), nausea (10%) and tachycardia (10%). All 10 patients proceeded to AHCT at a median of 12.5 days (range 8-17 days) after collection. Median times to neutrophil and platelet engraftment were 11 days (range 11-17 days) and 15 days (range 11-27 days), respectively. Conclusions Burixafor, in combination with propranolol and G-CSF, demonstrated an excellent safety profile and effectively mobilized sufficient HPCs for AHCT, including patients previously treated with lenalidomide and daratumumab. Notably, burixafor enabled same-day administration with leukapheresis, offering a key advantage over other CXCR4 inhibitors, such as plerixafor and motixafortide through its rapid mobilization kinetics. Its favorable safety profile, characterized by minimal adverse events, supporting its potential clinical utility.