This phase I trial studies the side effects and best dose of pacritinib when given together with venetoclax and azacitidine in treating patients with accelerated and blast phase myeloproliferative neoplasms (MPN-AP/BP). Pacritinib and azacitidine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving pacritinib together with venetoclax and azacitidine may be safe, tolerable, and/or effective in treating patients with MPN-AP/BP

PRIMARY OBJECTIVE:

I. To estimate the maximum tolerated dose (MTD) of pacritinib when used in combination with venetoclax and azacitidine in subjects with MPN-AP/BP.

SECONDARY OBJECTIVES:

I. To evaluate the frequency and nature of adverse events of the combination of venetoclax, azacitidine, and pacritinib in subjects with accelerated and blast phase myeloproliferative neoplasms (MPN-AP/BP).

II. To estimate the rate of responses as defined by European LeukemiaNet (ELN) 2022 response criteria for acute myeloid leukemia (AML).

III. To estimate the rate of responses as defined by Post-Myeloproliferative Neoplasm (MPN) AML Consortium 2012 criteria.

IV. To estimate the average reduction in spleen volume from baseline to week 12 and week 24 OUTLINE: This is a dose-escalation study of pacritinib in combination with venetoclax and azacitidine.

Patients receive pacritinib orally (PO) once daily (QD) or twice daily (BID) on days 1-28 of each cycle, venetoclax PO QD on days 1-21 of each cycle, and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo magnetic resonance imaging (MRI) or computed tomography (CT) as well as bone marrow aspiration and biopsy throughout the trial. Patients also undergo blood sample collection on study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 1 year from the start of treatment.

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Subjects must have accelerated phase MPN as defined by 10-19% blasts or blast phase MPN (AML) as defined by ≥ 20% blasts in the blood or bone marrow by manual aspirate differential, immunohistochemistry staining, or flow cytometry, with a documented prior diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), or primary myelofibrosis (PMF), The absence of a spleen, lack of splenomegaly, or history of splenic irradiation is not exclusionary.
• Subjects with blast phase MPN must be newly diagnosed/untreated (no prior blast reduction therapy for blast phase disease except for hydroxyurea and/or a JAK inhibitor; treatment of a prior accelerated phase is allowed). Prior treatment with a hypomethylating agent (with or without a JAK inhibitor) is allowed for accelerated phase MPN. Prior treatment with any JAK inhibitor (including pacritinib) is allowed for any phase of disease (chronic, accelerated, or blast); however, must not have discontinued pacritinib due to toxicity. If a participant previously required dose reduction during pacritinib therapy and tolerated it well, then may enroll into a cohort utilizing that dose level or lower.
• WBC < 25 x 109/L prior to treatment initiation- subjects with WBC ≥ 25 x 109/L may still be eligible after receiving cytoreduction measures such as hydroxyurea and/or leukapheresis if WBC becomes < 25 x 109/L prior to treatment initiation. Cytoreduction with hydroxyurea and/or leukapheresis is allowed prior to treatment. Hydroxyurea must be discontinued ≥ 12 hours prior to treatment initiation.
• Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration:
• Total bilirubin: ≤ 1.5 x upper limit of normal (ULN) unless considered to be due to Gilbert's Syndrome, hemolysis, or leukemic organ involvement. Total bilirubin WBC < 25 x 109/L prior to treatment initiation- subjects with WBC ≥ 25 x 109/L may still be eligible after receiving cytoreduction measures such as hydroxyurea and/or leukapheresis if WBC becomes < 25 x 109/L prior to treatment initiation. Cytoreduction with hydroxyurea and/or leukapheresis is allowed prior to treatment. Hydroxyurea must be discontinued ≥ 12 hours prior to treatment initiation.
• Demonstrate adequate organ function as defined below. All screening labs to be obtained within 28 days prior to registration:
• Total bilirubin: ≤ 1.5 x upper limit of normal (ULN) unless considered to be due to Gilbert's Syndrome, hemolysis, or leukemic organ involvement. Total bilirubin must be < 3 x upper limit normal in subjects with Gilbert's Syndrome, hemolysis, or leukemic organ involvement.
• Aspartate aminotransferase (AST): ≤ 3 x ULN (≤ 5 x ULN if considered to be due to myelofibrosis or leukemic organ involvement).
• Alanine aminotransferase (ALT): ≤ 3 x ULN (≤ 5 x ULN if considered to be due to myelofibrosis or leukemic organ involvement).
• Creatinine clearance: ≥ 30 mL/min by Cockcroft-gault formula or measured by 24-hour urine collection.
• Participants of child-bearing potential must agree to use highly effective contraceptive methods prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

Exclusion Criteria:

• Diagnosis of de novo AML, acute promyelocytic leukemia, or accelerated or blast phase MPN without a documented prior diagnosis of ET, PV, or PMF.
• Known CNS leukemia involvement. NOTE: Subjects with clinical suspicion or signs of neurologic deficit should undergo a screening lumbar puncture prior to enrollment to confirm lack of CNS leukemia.
• Previous treatment with BCL-2/BCL-X inhibitors (including venetoclax and navitoclax).
• Prior allogeneic stem cell transplantation for blast phase disease. Prior allogeneic stem cell transplantation for chronic and accelerated phase MPN is allowed. Subjects must not have received transplant within 60 days. Cannot be receiving immunosuppression therapy, with the exception of prednisone ≤10mg/d (or equivalent), for the treatment or prophylaxis of GVHD. If the subject has been on immunosuppressant treatment or prophylaxis for GVHD, the treatment must have been discontinued at least 14 days prior to study treatment and there must be no evidence of Grade ≥ 2 GVHD.
• Treatment with moderate or strong CYP3A4 inhibitors or strong CYP3A4 inducers within five half-lives or 14 days, whichever is shorter, prior to the initiation of study treatment.

Treatment with chemotherapy, wide-field radiation, or biologic therapy, with the exception of hydroxyurea as above, and all trans-retinoic acid given initially for presumed APML, within 14 days of study entry. Prior JAK inhibitor (other than pacritinib) must be held for five half-lives prior to study entry. Administration of steroids to prevent withdrawal symptoms is allowed.

• Treatment with investigational drug within five half-lives or 14 days, whichever is shorter, prior to study entry.
• Baseline prolonged QTc of > 480 msec. QTc measured by Fridericia's formula (QTc=QT/[RR1/3]) based on the mean of triplicate reads. Repeat EKGs after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria.
• Grade ≥2 bleeding event within the previous 3 months. Treatment with anticoagulation or antiplatelet agents (except for aspirin at dosages ≤100 mg per day or prophylactic doses of enoxaparin or heparin) within five half-lives or 7 days, whichever is shorter.
• Any GI or metabolic condition that could interfere with absorption of oral medication.
• Known severe (Child-Turcotte-Pugh class C) hepatic cirrhosis. Testing not required.
• Pre-existing uncontrolled pathology such as heart failure (congestive/ischemic, NYHA classes III and IV), clinically significant abnormalities on a 12-lead electrocardiogram, significant pulmonary disease, severe/unstable arrhythmias/angina pectoris/hypertension, acute or chronic pancreatitis, etc. Acute myocardial infarction or stroke within 6 months of study entry.
• Known active HIV, Hepatitis B, or Hepatitis C infection; testing not required.
• Active uncontrolled or severe systemic infection. Enrollment is possible after control of infection, at discretion of the treating physician.
• History of another active malignancy in the previous 2 years, with the exception of:

adequately treated in situ carcinoma of the cervix, breast, prostate; basal cell carcinoma pf the skin or localized squamous cell carcinoma of the skin.

• Pregnant or nursing female participants