A Multicenter Phase 1/2 Clinical Trial of Tagraxofusp, a CD123-Targeted Therapy, in Patients with Poor-Risk Primary and Secondary Myelofibrosis

Study Rationale:
At present there are no effective therapies for patients with primary or secondary myelofibrosis (MF) after the failure of the JAK inhibitory class of therapies. Furthermore, patients with monocytosis, thrombocytopenia, accelerated phase, or high-risk genetic features fare poorly with JAK inhibitors (JAKi), as intolerance, resistance, and/or ineligibility often limit treatment options. Median overall survival in most studies post-JAKi demonstrate poor outcomes (14-28 months) among patients with MF. Consequently, there is a considerable need in identifying new therapeutic targets beyond JAK-STAT inhibition. One potential cancer target is CD123, aberrantly expressed on leukemia stem cells and aberrant/malignant microenvironmental plasmacytoid dendritic cells (pDC) in certain myeloid cancers including MF. Tagraxofusp (TAG), a CD123-targeted therapy FDA-approved for patients with blastic plasmacytoid dendritic cell neoplasm, a pDC-derived malignancy, has demonstrated preclinical proof-of-concept in MF. We now report the updated results of an ongoing study of TAG monotherapy in patients with relapsed/refractory MF, or who were unable to tolerate currently approved JAKi. (NCT02268253)

Experimental Design:
A multicenter Phase 1/2 trial with TAG administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1-3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8⁺) in stage 1, and 12 mcg/kg every 21 days (C1-4), 28 days (C5+) in the currently ongoing stage 2.

Results:
Thirty-five patients (pts) with a median age 69 years (range: 54-87) have been treated thus far: 26% had baseline monocytosis and 69% had baseline thrombocytopenia, which impacts optimal dosing of JAKi, including 37% with platelets <50x10⁹/L including 7 pts with platelets ≤20; 75% had baseline palpable splenomegaly. Baseline genomic analysis in 35 pts revealed: JAK2 V617F (n=21); CALR (n=3); MPL (n=2); 7 of 21 pts who had comprehensive NGS, had an ASXL1 mutation. Most common treatment-related adverse events (incidence ≥15%) include hypoalbuminemia (23%), headache (17%), and elevated alanine aminotransferase (17%). Notably, capillary leak syndrome (CLS) was reported in 3 pts (1 was grade 4). Twenty-one pts (60%) achieved stable disease (SD) by IWG-MRT revised 2013 criteria, including 4 who had substantial clinical benefits; SD was noted in 7 of 9 (78%) with monocytosis, 7 of 13 (54%) with baseline platelets ≤50x10⁹/L, including 3 of 7 (43%) with baseline platelets ≤20x10⁹/L, and 2 of 3 (67%) pts with accelerated phase. At week 24, spleen responses by palpation were observed in 10 (45%), including 2 with >50% spleen reduction; 12 of 26 (46%) had symptom burden reduction, including 3 pts who met the IWG-MRT criteria. There have been three deaths, all deemed to be unrelated to study drug, occurring in cycles 1, 6, 13, respectively. The median overall survival of our cohort was 31 months (range: 0.6-42 months).

Conclusions:
Interim results demonstrate clinical efficacy and safety of TAG monotherapy in JAKi relapse/refractory/intolerant MF patients, including those associated with recognized poor-risk biological and clinical features, such as monocytosis. Some patients have experienced clinical benefit, including reduction in splenomegaly and improvement in quality of life and enrollment continues.