Pacritinib in CMML

Inclusion Criteria:

• Participants must be ≥18 years of age at time of signing the Informed Consent Form (ICF).

• Participants must voluntarily sign an ICF.

• Participants must have a pathologically confirmed diagnosis of chronicmyelomonocytic leukemia per World Health Organization (WHO) or InternationalConsensus Classification (ICC)

• Participants must be JAK inhibitor naïve.

• Participants may be hypomethylating agent (HMA) naïve or can be treated with up toone prior cycle.

• Participants must have either proliferative CMML (WBC ≥13 x 109/L) or haveintermediate-2 or high risk CMML by the clinical/molecular CMML-specific prognosticscoring system (CPSS-Mol).

• Participants must have a life expectancy of at least 24 weeks per investigator.

• ECOG performance status ≤ 3.

• Females of reproductive potential should use effective contraception duringtreatment with azacitidine and for 6 months after the last dose and males withfemale partners of reproductive potential should use effective contraception duringtreatment with azacitidine and for 3 months after the last dose.

• Male participants should agree to use an adequate method of contraception startingwith the first dose of study therapy through 90 days after the last dose of studytherapy.

• Must have adequate organ function as demonstrated by the following:

• Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless considered dueto leukemic organ involvement, Gilbert's syndrome, or hemolysis.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 xULN.

• Creatinine clearance (CrCl) of ≥30 mL/min.

• PT or INR <=1.5x ULN and PTT or aPTT <=1.5x ULN.

• ANC >= 500 cells/μL.

• Ability to adhere to the study visit schedule and all protocol requirements.

• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 2 weeks or within 5 half-lives of the priorinvestigational agent, whichever is shorter, of the first dose of treatment.

• Active Graft Versus Host Disease (GVHD), or any GVHD requiring treatment withimmunosuppression, with the exception of topical steroids and systemic steroids at adose equivalent to prednisone 10mg or less and at a stable or decreasing dose. AnyGVHD treatment (including calcineurin inhibitors) must be discontinued at least 28days prior to Day 1 of study treatment.

• Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP450 inducer within 14 days prior to treatment Day 1 (see Appendix 13.7 and 13.8 for a list of CYP3A4inhibitors and CYP450 inducers, respectively). Shorter washout periods may bepermitted with approval of the Study Chair, provided that the washout period is atleast five half-lives of the drug prior to treatment Day 1.

• Other invasive malignancies within the last 3 years, except curatively treatednon-melanoma skin cancer, localized prostate, cervical cancer, and any curativelytreated carcinoma in situ.

• Presence of active serious infection.

• If a patient is identified to have COVID-19 during the screening period,participants may be considered eligible if in the opinion of the investigatorthere are no COVID-19 sequlae that may place the patient at a higher risk ofreceiving investigational treatment.

• Any serious, unstable medical or psychiatric condition that would prevent, (asjudged by the Investigator) the patient from signing the informed consent form orany condition, including the presence of laboratory abnormalities, which places thepatient at unacceptable risk if he/she were to participate in the study or confoundsthe ability to interpret data from the study.

• Known history of uncontrolled human immunodeficiency virus (HIV).

• Significant recent bleeding history defined as NCI CTCAE grade ≥2 within 3 monthsprior to treatment Day 1, unless precipitated by an inciting event (e.g., surgery,trauma, or injury).

• Systemic treatment with medications that increase the risk of bleeding, includinganticoagulants, antiplatelet agents (except for aspirin dosages of ≤100 mg per day),anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1inhibiting Non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior totreatment Day 1.

• Any history of CTCAE grade ≥2 cardiac conditions within 6 months prior to treatmentDay 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditionsmay be considered for inclusion, with the approval of the Study Chair, if stable andunlikely to affect patient safety.

• Heart failure other than NYHA class I (asymptomatic, without limitation).

• QT corrected by the Fridericia method (QTcF) prolongation >480 ms or other factorsthat increase the risk for QT interval prolongation (e.g., hypokalemia [defined asserum potassium <3.0 mEq/L that is persistent and refractory to correction], orhistory of long QT interval syndrome).

• Known active systemic hepatitis B, or C infection requiring therapy or knowncirrhosis.

• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling,or child) who is investigational site or pharmaceutical sponsor staff directlyinvolved with this trial, unless prospective IRB approval (by chair or designee) isgiven allowing exception to this criterion for a specific participant.

• Organ transplant recipients other than bone marrow transplant.

• Women who are pregnant or lactating.

• Patient with known gastrointestinal (GI) disease or prior GI procedure that couldinterfere with the oral absorption or tolerance of pacritinib, including difficultyswallowing, are not eligible.