A Phase Ib, Open-Label Study of Add on Therapy with CK0804 in Participants with Myelofibrosis and Suboptimal Response to Ruxolitinib

Background: Deregulated inflammatory pathways including CXCR4/CXCR12 axis might contribute to suboptimal therapeutic efficacy of ruxolitinib in myelofibrosis (MF) and ultimate disease progression. In preclinical studies, cord blood-derived, CXCR4 enriched T regulatory cells [CK0804; T-regs] showed ability to suppress inflammatory cytokines which play major role in MF pathogenesis (Huang et al., iScience, 2024). Methods: This phase Ib study evaluates the safety and activity of up to 6 doses of CK0804 (non-HLA matched, Cryopreserved) T-regs therapy, fixed dose of 100 million cells, added every 28 days to steady dose ruxolitinib. Patients with MF on ruxolitinib for at least 12 weeks and stable dose for 8 weeks, who have palpable splenomegaly, symptoms, or grade 2 cytopenia are eligible. Primary and secondary objective includes safety and overall response per IWG-MRT criteria at 24 weeks, respectively. Present analysis includes completed initial safety cohort. Results: The safety run-in cohort enrolled all planned 9 patients (median age 68 years; range, 55-84; 44% males). At study initiation, median [range] white cells x10^9/L, hemoglobin g/dL and platelets x10^9/L were 10.6 [3.1-70.4], 8.8 [7.8-11.5] and 177 [148-311], respectively. Three patients were transfusion dependent. Median spleen volume was 1449 cubic centimeters (range, 176-5609) where 7 patients (78%) had clinically progressing splenomegaly. Median symptoms score (MPN-SAF TSS) was 23 (range, 20-40). Six (67%) had diploid karyotype, 5 (56%) had JAK2 mutation and 8 (89%) had additional no-driver mutations. Median duration of prior ruxolitinib was 35 months (range, 10-132). All patients were on 10 mg twice daily dose or higher and continued on the same dose throughout the study. Seven patients received all six doses of CK0804. One patient experienced infusion reaction to second dose of CK0804 likely due to excipient dimethylsulfoxide and withdrew consent. One patient died of unrelated cause prior to infusion #6. There were no non-hematologic or hematologic adverse events. Two PRBC transfusion dependent patients who were evaluable for response had reduction in their monthly need for transfusions by the end of the sixth cycle of CK0804: 4 to 2.8 units/month and 1.2 to 0.8 units/month, respectively. All patients noticed symptoms improvement. Using Bayesian one-way ANOVA, the mean MPN-SAF TSS score (95% CI) was 6.25 (4.9-7.6) at baseline, which decreased to 3.5 (2.9-4.1) at C4D1 and 4.3 (2.8-5.8) at EOC6 (p=0.3). The Fatigue subset score was 6.2 (4.8-7.6) at baseline, which decreased to 3.5 (2.1-4.9) at C4D1 and 4.3 (2.8-5.8) at EOC 6 (p=0.02). The median best decline in MPN-SAF TSS was -38% (range, -20% to -71%); with ³50% reduction in 4 patients. Four out of 6 evaluable patients had spleen volume reduction (SVR), where one patient achieved more than 35% reduction in SVR at week 12, maintained at week 24. Longitudinal analysis of markers of inflammation and follow up data after the 6^th infusion showing sustained benefit (including improvements in hemoglobin) will be reported at the conference. Conclusion: This preliminary analysis of run-in phase of study evaluating CXCR4 enriched T regs cell therapy as addition to ruxolitinib shows initial safety with no myelosuppressive adverse events and promising clinical activity.