Targeting Danger Associated Molecular Pattern (DAMP) with CD24Fc to Reduce Acute Gvhd: Study Design on a Randomized Double Blind Placebo Controlled Phase III Clinical Trial (CATHY Study)

Introduction Allogeneic HCT is the only established curative therapy for high risk hematologic malignancies. The major challenges are leukemia relapse and high grade GVHD. We have developed the CD24Fc fusion protein to selectively inhibit danger-associated molecular pattern (DAMP)-induced inflammation and discovered that it effectively prevents GVHD without affecting the desirable GVL effect in preclinical models. With the support of SBIR awards from the NCI, we have completed a phase II randomized, double blind, multi-center, dose escalation trial comprised of 3 dosing cohorts of 8 patients (3:1 CD24Fc vs. placebo), with a total enrollment of 24 subjects. Notably, clinical data from this trial demonstrate that CD24Fc reduces the incidence of severe GVHD, resulting in statistically significant increases of acute 180-day GVHD-free survival (aGFS). A Phase II expansion cohort to enroll an additional 20 subject is ongoing (NCT02663622). Here we propose a phase III clinical trial with 180 patients (1:1 CD24Fc vs placebo) to test the hypothesis that CD24Fc prophylaxis can significantly improve 180 day acute GVHD-free survival (aGFS) over placebo control. Study Design A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of CD24Fc for the Prevention of Acute GVHD Following Myeloablative Allogeneic HCT (CATHY) (NCT04095858). This study will compare CD24Fc or Placebo with standard GVHD prophylaxis of tacrolimus and methotrexate in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic HCT in patients with AML/ALL or MDS. Patients will be randomized 1:1 to receive CD24Fc or placebo at the dose levels of 480mg, 240mg and 240mg on Days -1, +14 and +28, respectively. The primary endpoint is the rate of 180 days grade III-IV acute GVHD-free survival (aGFS). Secondary endpoints are 1 yr DFS, 1 yr OS, and D180 Gr II-IV aGFS. Other exploratory evaluations will be 1 yr chronic GVHD, 1 yr relapse, NRM at 1 year, incidence and rate of infection at 100 days, and rate of Gr III and above mucositis at 28 days. The study will enroll 180 patients, or 90 per arm, with an estimated accrual period of 24 months. Statistical Consideration The study will include one interim analysis for efficacy. Z test statistics for comparing the two arms will be compared to the critical values and results be reviewed by the independent DSMB.