Pacritinib in CMML

This is a phase 1/2 trial of pacritinib in combination with azacitidine in patients with Chronic Myelomonocytic Leukemia (CMML). Patients will be newly diagnosed or previously treated but could not have received a prior JAK inhibitor. Patients who have previously been treated with a hypomethylating agent (HMA) must have received ≤ 1 cycle. Pacritinib will be initially tested at a dose of 200mg twice daily (dose level 0) in combination with azacitidine 75mg/m2, which can be administered subcutaneously or intravenously, for 7 days in a 28-day cycle. If there are 2 DLTs in the first 6 patients, there will be a dose escalation to pacritinib 100mg twice daily (dose level -1) and an additional 6 patients will be enrolled. Based on the phase 1, 3+3 dose de-escalation design, 6-12 patients will be enrolled in the phase 1 portion. After the completion of phase 1 and identification of the recommended phase 2 dose (RP2D), the trial will then proceed to phase 2 which will employ a Simon two stage design. This portion will include the 6 patients enrolled during the phase 1 portion at the MTD. An interim analysis for futility will occur. If 3 or fewer patients have had a clinical benefit (CB) or better, as defined by 2015 MDS/MPN IWG criteria, the PI and DSMC will meet to discuss the totality of the evidence and determine if the trial shall proceed. In the second stage, an additional 12 patients will be enrolled.

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 chronic myelomonocytic leukemia per World Health Organization (WHO) or International Consensus Classification (ICC) * Participants must be JAK inhibitor naïve. * Participants may be hypomethylating agent (HMA) naïve or can be treated with up to one prior cycle. * Participants must have either proliferative CMML (WBC ≥13 x 109/L) or have intermediate-2 or high risk CMML by the clinical/molecular CMML-specific prognostic scoring 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 during treatment with azacitidine and for 6 months after the last dose and males with female partners of reproductive potential should use effective contraception during treatment with azacitidine and for 3 months after the last dose. * Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy. * Must have adequate organ function as demonstrated by the following: * Serum total bilirubin ≤ 2.0 x upper limit of normal (ULN) unless considered due to leukemic organ involvement, Gilbert's syndrome, or hemolysis. * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN. * Creatinine clearance (CrCl) of ≥30 mL/min. * PT or INR \480 ms or other factors that increase the risk for QT interval prolongation (e.g., hypokalemia \[defined as serum potassium \