Pilot Phase II Trial of the Combination of Tagraxofusp with Pacritinib in Patients with Myelofibrosis, Tagpac Study
Authors: Yacoub Abdulraheem , Lin Tara L. , Male Heather J , Byrd Kenneth P , Abdelhakim Haitham , Stewart Lisa , Jensen Maddie , Gonzalez Lugo Jesus D 
Published: December 2024

Background: Myelofibrosis (MF) is a chronic myeloid malignancy characterized by a variable presentation of symptom burden, splenomegaly, cytopenias and increased risk of mortality and transformation to acute leukemia. Therapy with JAK inhibitors was developed based on the discovery and characterization of the biological driver role of the overactive JAK-STAT signaling in the pathophysiology of MF. Multiple JAK inhibitors have been approved for MF based on activity in spleen volume reduction, symptoms improvement, and additional clinical benefits that are unique to each agent. None of the approved JAK inhibitors have demonstrated complete clinical or pathological responses, deep molecular responses, or true disease modification. Patients who respond initially inevitably will lose response and progress requiring subsequent therapy. Multiple combinations with JAK inhibitors have been investigated in Phase II and Phase III clinical trials. Some have shown potential additive clinical benefit but have not met regulatory approval thresholds. Pacritinib (PAC) is an FDA approved JAK2/IRAK1/ACVR1 inhibitor that was studied in treatment naïve and JAK-inhibitor exposed patients and demonstrated benefit in spleen reduction, symptom improvement, improvement in anemia endpoints, and less myelosuppressive particularly in regard to platelet count. Tagraxofusp (TAG) is a recombinant fusion protein comprised of human IL-3 and truncated diphtheria toxin that targets the IL-3R (CD123) and is FDA approved for therapy in blastic plasmacytoid dendritic cell neoplasm (BPDCN). TAG was studies in MF in Phase I/II study that identified optimum dosing in MF and showed symptoms improvement, modest spleen reduction, and observed survival that exceeded historic reports. The combination of TAG and PAC has not been studied.

Design and Methods: The primary objective of this open label, single-center, pilot study (NCT06414681) is to characterize the efficacy of the combination of Tagraxofusp and Pacritinib in patients with MF. The two primary end points are reduction of spleen volume at week 24 by imaging and reduction in symptoms at week 24 as measured by the MPN-SAF TSS 2.0. Key secondary endpoints include safety and feasibility of the combination, hematologic improvement and molecular responses in study subjects. Key eligibility criteria include a confirmed diagnosis of primary MF or post-PV/ET MF; intermediate-2/high-risk disease by clinical prognostic scores; relapsed/refractory after prior therapy with an approved JAK inhibitor or in which therapy with other JAK inhibitors is not appropriate, contraindicated or declined by the subjects; and the presence of indication for therapy as defined by protocol. TAG will be administered at 12 mcg/kg IV infusion once daily for 3 consecutive days and PAC will be given orally, 200 mg twice per day starting at C2D4 and administered continuously. Treatment cycles will be every 21 days for 4 cycles then every 28 days thereafter, and adverse events will be graded according to the NCI CTCAE v. 5.0. We expect to enroll the first patient in this trial in August of 2024. We plan to enroll 10 subjects and based on observed efficacy and safety results to expand to 20 subjects.