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 Stem Cells in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant

Background and Significance:

Autologous stem cell transplant (ASCT) plays a central role in the treatment of multiple myeloma (MM). However, poor hematopoietic progenitor cell (HPC) mobilization occurs in 15-25% of patients. Newer therapies, such as daratumumab, may also have a negative impact on mobilization, supporting a need for an alternative mobilization regimen. Burixafor (GPC-100) is a potent and selective small molecule antagonist of CXCR4. Previous clinical trials with burixafor alone or in combination with G-CSF have demonstrated safe and effective mobilization of stem cells. Burixafor is characterized by faster kinetics of mobilization compared to the current FDA approved CXCR4 inhibitors, allowing same day administration and leukapheresis.

Propranolol, a non-selective beta-blocker, has been clinically shown to inhibit molecular risk markers in MM patients receiving ASCT. Other studies have also shown that propranolol can improve cellularity and reduce pro-tumorigenicity in the bone marrow. The aim of this study is to improve the health of the bone marrow stem cell niche and optimize mobilization in patients with MM eligible for HSCT.

Study Design and Methods:

This study (NCT05561751) is a U.S. only, open-label, multi-site Phase 2 trial. A total of 20 participants will be enrolled across 10 sites. The primary objective is to determine the proportion of patients that will achieve ≥2 x 10⁶ CD34+ cells/kg in 2 leukapheresis sessions. The study will employ a Bayesian Optimal Phase 2 (BOP2) design to characterize the safety and clinical activity of burixafor.

Participants self-administer 30 mg propranolol orally twice daily from Days 1 to 8 and receive SC injections of 10 ug/kg/day G-CSF in the afternoon on Days 3 to 7. On days 7 and 8, participants will receive 3.14 mg/kg dose of burixafor via IV and undergo leukapheresis 45 minutes post drug administration. Participants may undergo additional optional days of the treatment regimen and stem cell collection, per Investigator's discretion to meet institutional collection goal standards. Participants were monitored for adverse event until 28 days after the last dose of burixafor.

Results:

With enrollment still ongoing, four patients have enrolled to date. The median age was 67 years old (range 60-74 years old). The primary endpoint of ≥2 x 10⁶ CD34⁺ cells/kg in two apheresis sessions was achieved in all patients. 75% of these patients achieved ≥6 x 10⁶ CD34⁺ cells/kg in two apheresis sessions. Of these patients, 2 had received 4 cycles of Daratumumab-RVd. For the other 2 patients, one received 3 cycles of Dara-R and the other 4 cycles of RVd. A total of 45 adverse events (AE) of any grade were observed, 71% of which occurred after transplant. AEs related to GPC-100 were all grade 1 and include flushing, chest tightness, stomach pain, and nausea, as observed before. No incidence of diarrhea during the mobilization and leukapheresis period was reported. No AE related to propranolol was observed. All of the grade ≥3 AEs (18% of total AEs) occurred after transplant. All four patients proceeded to ASCT at a median of 8 days (range 6-10 days) after collection. Median time to neutrophil engraftment was 12 days (range 11-15 days).

Conclusions:

Preliminary data for burixafor in combination with propranolol and G-CSF is promising. Results suggest that the treatment regimen can mobilize CD34⁺ stem cells sufficiently for ASCT, including for patients who have been treated with daratumumab. Notably, burixafor allowed for same day administration of both mobilizing agent and leukapheresis. This quick kinetics of mobilization is differentiated from the FDA approved plerixafor or motixafortide, which require overnight pre-treatment prior to leukapheresis.

Caculitan:GPCR Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Kim:GPCR Therapeutics, Inc.: Current Employment, Current holder of stock options in a privately-held company. Akard:Novartis: Other: Consultant; Beigene: Honoraria. Khouri:GPCR Therapeutics, Inc.: Honoraria; Legend: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Consultant; Prothena: Honoraria. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Cardarelli:GPCR Therapeutics: Current Employment, Current holder of stock options in a privately-held company.

We are using propranolol, a non-selective beta blocker typically used for cardiovascular indications, to help improve the bone marrow stem cell niche prior to mobilization of stem cells with our own CXCR4 inhibitor, burixafor (GPC-100). The patient then undergoes leukapheresis to collect the stem cells for autologous stem cell transplant in multiple myeloma patients.