Summary Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative therapy for a broad spectrum of high risk leukemia and myelodysplasia in adults. However, approximately 40% of adult patients die within one year following HSCT, primarily due to leukemia relapse and grade III-IV graft versus host disease (GVHD). To combat these challenges, we have developed the CD24Fc fusion protein to selectively inhibit DAMPs (danger-associated molecular patterns)-induced inflammation and discovered that it effectively prevents GVHD without affecting the graft vs-leukemia (GVL) effect in preclinical models. With the support of a direct SBIR phase II award, we have completed a phase IIA randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (1:3 placebo:treatment), with a total enrollment of 24 subjects. Surprisingly, the data suggest that, in comparison to the placebo group and contemporary controls of HSCT patients receiving the same standard of care, CD24Fc not only reduced the incidence of severe GVHD, but also reduced the incidence of leukemia relapse, resulting in statistically significant increases in severe acute GVHD-free survival (AGFS) over 180 days and disease-free survival over 800 days. As result, we held an end of phase II meeting with the FDA who agreed that we are in a position to submit a protocol for a phase III clinical trial. In addition to the end of phase II meeting, we also had a teleconference with the FDA for their advice on an application for Breakthrough Therapy Designation (BTD). We were advised to perform an open- label phase II dose expansion trial using the same multiple dosing regimen from the phase IIA trial. Here we propose to perform the phase II dose expansion clinical trial involving a total of 20 patients to test the clinical hypothesis that CD24Fc prophylaxis can significantly improve 180 day AGFS over matched historical controls from the national database. Our proposed studies address the two most pressing medical needs for HSCT in leukemia patients with the potential to significantly improve survival of high risk leukemia patients and will thus have a transforming impact to HSCT. In addition, our study may allow the sponsor to receive Breakthrough Therapy Designation from the FDA and thus greatly accelerate the pace of the clinical development of CD24Fc for patient care.
Public Health Relevance Statement: Narrative Our proposed studies address the unmet medical need of high-risk leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) with the potential to significantly improve survival of high risk leukemia patients and will thus have a transforming impact to HSCT. In addition, our study may allow the sponsor to receive breakthrough therapy designation from the FDA and thus greatly accelerate the pace of the clinical development of CD24Fc for patient care.
NIH Spending Category: Cancer; Clinical Research; Clinical Trials and Supportive Activities; Comparative Effectiveness Research; Hematology; Orphan Drug; Patient Safety; Rare Diseases; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Human; Transplantation
Project Terms: Acute Graft Versus Host Disease; Address; Adult; Affect; Allogenic; Award; Blood; Bone Marrow Transplantation; Chimeric Proteins; Clinical; clinical development; Clinical Trials; cohort; combat; conditioning; curative treatments; Data; Databases; Disease-Free Survival; Dose; Double-Blind Method; Dysmyelopoietic Syndromes; efficacy testing; Enrollment; graft vs host disease; graft vs leukemia effect; Hematopoietic Stem Cell Transplantation; high risk; improved; Incidence; Infection; Inflammation; international center; leukemia; Medical; meetings; Methods; Molecular; open label; Outcome; Patient Care; Patient Monitoring; patient safety; Patients; Pattern; Phase; Phase III Clinical Trials; placebo group; Placebos; Positioning Attribute; Pre-Clinical Model; prevent; primary endpoint; Prophylactic treatment; prospective; Protocols documentation; Randomized; Regimen; Relapse; Research; secondary endpoint; Severities; Single-Blind Study; Small Business Innovation Research Grant; standard of care; Stem cells; Stratification; Teleconferences; Testing; Transplant Recipients
