A new phase 1 clinical trial investigating the combination of tagraxofusp and pacritinib has opened for patients with myelofibrosis (MF) who have limited treatment options after JAK inhibitor therapy.
The single-center, open-label pilot study aims to recruit 20 adult patients with MF who have previously been treated with a Janus kinase (JAK) 1/2 inhibitor or for whom such therapy is not appropriate, contraindicated, or declined by the patient.
Novel Therapeutic Approach for Treatment-Resistant Myelofibrosis
Myelofibrosis, a rare bone marrow cancer characterized by scarring of the bone marrow, progressive anemia, and enlarged spleen, affects approximately 1.5 per 100,000 people annually. Current treatment options are limited, with JAK inhibitors being the mainstay therapy, though many patients either fail to respond or lose response over time.
The trial's treatment protocol involves administering 12 μg/kg of intravenous tagraxofusp once daily for 3 consecutive days, followed by 200 mg of oral pacritinib twice daily starting on the 4th day of the second cycle. Pacritinib will then be administered continuously with subsequent cycles beginning on day 1 of each cycle.
"The rationale behind combining these two agents lies in their complementary mechanisms of action," explains the lead investigator. "Tagraxofusp is a cytotoxin directed at CD123, while pacritinib is a small-molecule kinase inhibitor. Together, they target MF stem cells and the bone marrow environment in ways that could potentially overcome resistance to standard JAK inhibitor therapy."
Clinical Endpoints and Patient Assessment
The trial has established two primary outcome measures to evaluate efficacy:
- Spleen volume reduction of 35% or more from baseline to week 24
- Change in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score Version 2.0 (MPN-SAF TSS 2.0) from baseline to week 24
Secondary outcome measures will assess safety through monitoring treatment-related adverse events, changes in anemia and platelet counts from baseline, and improvements in patients' quality of life based on global impression of change.
Scientific Rationale and Previous Evidence
Both agents have demonstrated promising activity individually in myeloproliferative neoplasms. Previous studies of these compounds in patients with mildly depleted bone marrow showed acceptable safety profiles and led to hematological improvements.
"The scientific hypothesis is that this combination may lead to significant improvements in symptoms associated with myeloproliferative neoplasms and reduce splenomegaly through dual-targeting mechanisms," notes a hematology expert familiar with the trial design. "Tagraxofusp targets the CD123 antigen expressed on MF stem cells, while pacritinib inhibits JAK2, FLT3, IRAK1, and CSF1R without causing significant myelosuppression."
This approach is particularly significant given the limited options for patients who fail JAK inhibitor therapy. Current data indicates that median survival after JAK inhibitor failure is approximately 14 months, highlighting the urgent need for new therapeutic strategies.
Context Within the MF Treatment Landscape
This trial comes at a time of significant advancement in MF treatment options. Recent data from the phase 3 MANIFEST-2 trial showed that pelabresib (CPI 0610) in combination with ruxolitinib significantly improved spleen responses compared with placebo/ruxolitinib in JAK inhibitor-naïve patients (65.9% vs 35.2% spleen volume reduction).
Other investigational approaches include selinexor plus ruxolitinib in the phase 1/3 XPORT-MF-034 trial for JAK inhibitor-naïve patients, and fedratinib maintenance therapy following allogeneic hematopoietic cell transplant.
"What distinguishes this trial is its focus on the post-JAK inhibitor setting, where effective options are extremely limited," comments a clinical researcher not involved in the study. "The combination of tagraxofusp and pacritinib represents a novel approach targeting multiple pathways involved in MF pathogenesis."
Trial Timeline and Future Implications
The trial is currently in its initial phase and aims to complete enrollment of 20 participants. The estimated completion date is December 2026, with interim analyses planned to assess early signals of efficacy and safety.
If successful, this combination therapy could provide a much-needed treatment option for patients with myelofibrosis who have exhausted or cannot tolerate standard therapies. The investigators hope that targeting both MF stem cells and the bone marrow microenvironment will lead to more durable responses than single-agent approaches.
Healthcare professionals interested in referring patients to this trial should note the specific inclusion criteria requiring prior JAK inhibitor exposure or contraindication to such therapy.
