The goal of this open-label, single-center, pilot trial is to test the combination of Tagraxofusp (TAG) with Pacritinib (PAC) in patients with intermediate-II or higher myelofibrosis (MF), who have had prior therapy with the approved JAK1/2 inhibitor or in which therapy with the approved JAK1/2 inhibitors is not appropriate, contraindicated or declined by the subjects.

The Primary Objective is to:

1. Characterized efficacy of the combination of Tagraxofusp and Pacritinib.

The Secondary Objective is to:

1. characterize the safety profile of the combination Tagraxofusp and Pacritinib.

2, Characterize the feasibility of the combination Tagraxofusp and Pacritinib. 3. Characterize hematologic improvement with the combination Tagraxofusp and Pacritinib.

4. Evaluate and compare the effect of Tagraxofusp and Pacritinib on participant reports of MF symptoms.

Exploratory:

Pharmacokinetic (PK) testing of Tagraxofusp and Pacritinib to assess clinical predictors of response.

Next Generation Sequencing (NGS) Testing to define the number and the allele burden of pathological mutations, as well as the changes over the course of therapy, both in regard to progression and response.

Blood will be collected and stored at KU BRCF for future study related PK analysis

A combination of these agent provides rational scientific merit and compatible mechanisms of action by targeting myelofibrosis stem cells and BM environment, in combination with effective JAK2 and IRAK1 inhibition resulting in improvement in MPN related symptoms and splenomegaly without overlapping toxicities. Both agents have been studied in mildly depleted bone marrow phenotypes showing safety and hematological improvements

Inclusion Criteria:

1. Ability of participant OR Legally Authorized Representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent.

2. The participant or LAR has signed informed consent prior to initiation of any study-specific procedures or treatment.

3. The patient is able to adhere to the study visit schedule and other protocol requirements.

4. Males and females age ≥ 18 years.

5. ECOG Performance Status 0 - 2 (Appendix A).

6. Life expectancy of > 6 months.

7. Patient meets the 2016 WHO diagnostic criteria for MF and has an IPSS/DIPSS/DIPSS-plus intermediate-II or higher-risk disease.

8. Patients who have indications for therapy per investigator or patient's choice, such as Splenomegaly, >5 CM BCM or mTSS ≥ 8 or mTSS Itching, night sweats, or bone pain ≥ 5 or Significant cytopenias including Hgb <10 g/dl, Platelet count less than 75 k/UL

9. Patients treated with a JAK inhibitor for >3 months and:

   had inadequate response to treatment, i.e., < 10% reduction of spleen by imaging, or less than 25% reduction by spleen length on physical exam or lack of control of MF symptoms that is not satisfactory to the patient. NOTE: Participants who had contraindication to therapy with the approved JAK inhibitor including subject's refusal of therapy are eligible.

10. A least 4 weeks have elapsed between the last dose of any MF-directed drug treatments, including hydroxyurea (HU), Interferon or glucocorticosteroids. NOTE: If patient is on a stable dose of glucocorticosteroids for another indication, they will be allowed into this study, AND patients on a stable dose of erythropoiesis-stimulating agents (ESA) are allowed on the study.

11. Patient is not eligible for an immediate allo-SCT.

12. Adequate baseline organ, cardiac, and renal function as defined by:

    LVEF ≥ 50% by ECHO within 6 months of study treatment initiation No clinically significant abnormalities on a 12-lead ECG, and no QTcF ≥ 480 msec Serum creatinine ≤ 1.5 mg/dL Serum albumin ≥ 3.2 g/dL (Note: albumin infusions are not permitted to enable eligibility) INR and PTT ≤ 1.5x ULN Albumin Supplementation Prior to the first dose, participant must have serum albumin ≥ to 3.2 g/dL.

    Note- for any participants with serum albumin ≤ to 4.0 g/dL, it will be advisable but up to physician's discretion to administer 25g increments of albumin infusion before the first dose.

    Total bilirubin ≤ 4x ULN AST and ALT ≤ 5 x ULN ANC ≥ 0.5 x 109/L PT or INR and PTT < = 1.5 x ULN

13. If the patient is a woman of child-bearing potential (WOCBP), they should have a negative serum pregnancy test no more than 7 days prior to start of treatment.

    (Note: WOCBP include any female who has experienced menarche and who has not undergone successful sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy with documented serum follicle stimulating hormone level ≥ 35 mIU/mL).

14. Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and for 3 months following completion of therapy.

Exclusion Criteria:

1. Simultaneously enrolled in any therapeutic clinical trial

2. Current or anticipating use of other anti-neoplastic or investigational agents while participating in this study.

3. The patient has received treatment with chemotherapy, wide-field radiation, or biologic therapy within 14 days of study entry.

4. The patient has received treatment with another investigational agent within 14 days of study entry.

5. Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements.

6. Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation.

7. Any condition or other contraindication to therapy as deemed by the principal investigator to place the subject at an unacceptably high risk for toxicities.

8. Is pregnant or breastfeeding.

9. Has a known allergic reaction to any excipient contained in the study drug formulation.

10. Active Grade 3 (per the NCI CTCAE, Version 5.0) or higher viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study treatment.

11. Prior therapy with Tagraxofusp or Pacritinib.

12. Presence of peripheral blood or bone marrow blast count > 10%

13. Active Graft versus Host Disease (GVHD)

14. For patients who have previously had Stem Cell Therapy (SCT) - The patient is receiving immunosuppressive therapy.

    EXCEPTION: low-dose prednisone (≤10 mg/day) - for treatment or prophylaxis of graft-versus-host disease (GVHD). If the patient has been on immunosuppressive treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at least 14 days prior to study treatment and there must be no evidence of Grade ≥ 2 GVHD.

15. Other uncontrolled active malignancy as determined by the principal investigator

16. The patient has an active malignancy and/or cancer history that may confound the assessment of the study endpoints. Patients with a past cancer history (within 2 years of entry) with substantial potential for recurrence and/or ongoing active malignancy must be discussed with the Sponsor before study entry. Patients with the following neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, cervical intraepithelial neoplasia, organ-confined prostate cancer with no evidence of progressive disease.

17. The patient has clinically significant cardiovascular disease (e.g. uncontrolled or any New York Heart Association Class 2 or greater congestive heart failure, uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).

18. Any gastrointestinal or metabolic condition that could interfere with absorption of oral medication.

19. Prior therapy with Pacritinib (PAC) or Tagraxofusp (TAG).

20. The patient has persistent clinically significant toxicities Grade ≥ 2 from previous therapies, including cytotoxic chemotherapy, targeted therapies, biological therapies, or immunotherapies, not readily controlled by supportive measures (excluding alopecia, nausea, and fatigue).

21. The patient has uncontrolled, clinically significant pulmonary disease (e.g. chronic obstructive pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator would put the patient at significant risk for pulmonary complications during the study.

22. The patient has known active or suspected central nervous system (CNS) disease. If suspected, CNS disease should be ruled out with relevant imaging and/or examination of cerebrospinal fluid.

23. Current systemic treatment with strong or moderate CYP3A4 inhibitor or P450 inducer.

    EXCEPTION: Patients who discontinue this treatment by Day 14 before start of treatment (Day -14) or 5 half-lives, whichever is shorter.

24. Use of full-dose anticoagulation and use of anti-platelet therapy other than aspirin 81mg daily within 14 days prior to D1.

25. Recent unprovoked bleeding of grade ≥ 2 within the last 3 months prior to Day 1.

26. Active uncontrolled diarrhea or inflammatory bowel disease (IBD)

27. Known sero-positivity for Hepatitis A (HAV), Hepatitis B (HBV), Hepatitis C (HCV), Human Immunodeficiency Virus (HIV)

28. Patients with history of clinically significant bleeding or on anticoagulants

29. Patients with moderate (Child-Pugh B ) and severe (Child -Pugh C) hepatic impairment will not be enrolled in the study.

30. Patients with eGFR < 30 mL/min will not be enrolled