Pacritinib in Combination with Azacitidine for the Treatment of Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes

Inclusion Criteria

• Subjects must be >= 18 years of age at time of signing the informed consent form (ICF)
• Subjects must voluntarily sign an ICF
• Subjects must have a pathologically confirmed diagnosis of chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (also called MDS/MPN with neutrophilia), or myelodysplastic/myeloproliferative neoplasm, unclassifiable per World Health Organization (WHO) or International Consensus Classification (ICC)
• Subjects must be JAK inhibitor naive
• Subjects may be hypomethylating agent (HMA) naive or can be treated with up to one prior cycle
• Subjects who have chronic myelomonocytic leukemia (CMML) must have intermediate-1 or high risk CMML by the clinical/molecular CMML-specific prognostic scoring system (CPSS-Mol)
• Subjects who have atypical chronic myeloid leukemia (aCML) or MDS/MPN-unclassifiable (U) must warrant HMA therapy in the opinion of the investigator
• Subjects must have a life expectancy of at least 24 weeks per investigator
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3
• Females of reproductive potential should use highly 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 90 days after the last dose
• Male subjects 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
• 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 unless considered due to leukemic organ involvement
• Creatinine clearance (CrCl) of ≥ 30 mL/min
• Prothrombin time (PT) or international normalized ratio (INR) =< 1.5 x ULN and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• Absolute neutrophil count (ANC) >= 500 cells/uL
• 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 a study of an investigational agent and received study therapy or used an investigational device within 2 weeks or within 5 half-lives of the prior investigational agent, whichever is shorter, of the first dose of treatment
• Active graft versus host disease (GVHD), or any GVHD requiring treatment with immunosuppression, with the exception of topical steroids and systemic steroids at a dose equivalent to prednisone 10mg or less and at a stable or decreasing dose. Any GVHD treatment (including calcineurin inhibitors) must be discontinued at least 28 days prior to day 1 of study treatment
• Systemic treatment with a strong CYP3A4 inhibitor or a strong CYP3A4 inducer within 14 days prior to treatment day 1. Shorter washout periods may be permitted with approval of the study chair, provided that the washout period is at least five half-lives of the drug prior to treatment day 1
• Other invasive malignancies within the last 3 years, except curatively treated non-melanoma skin cancer, localized prostate, cervical cancer, and any curatively treated carcinoma in situ
• Presence of active serious infection * If a subject is identified to have coronavirus disease 19 (COVID-19) during the screening period, subjects may be considered eligible if in the opinion of the investigator there are no COVID-19 sequalae that may place the subject at a higher risk of receiving investigational treatment
• Any serious, unstable medical or psychiatric condition that would prevent, (as judged by the investigator) the subject from signing the informed consent form or any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
• Known history of uncontrolled human immunodeficiency virus (HIV)
• Significant recent bleeding history defined as National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2 within 3 months prior to treatment day 1, unless precipitated by an inciting event (eg, surgery, trauma, or injury)
• Systemic treatment with medications that increase the risk of bleeding, including anticoagulants, antiplatelet agents (except for aspirin dosages of ≤ 100 mg per day), anti-vascular endothelial growth factor (anti-VEGF) agents, and daily use of COX-1 inhibiting non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to treatment day 1
• Any history of CTCAE grade ≥ 2 cardiac conditions within 6 months prior to treatment day 1. Patients with asymptomatic grade 2 non-dysrhythmia cardiovascular conditions may be considered for inclusion, with the approval of the study chair, if stable and unlikely to affect patient safety
• Heart failure other than New York Heart Association (NYHA) class I (asymptomatic, without limitation)
• QT corrected by the Fridericia method (QTcF) prolongation > 480 ms or other factors that increase the risk for QT interval prolongation (eg, hypokalemia [defined as serum potassium < 3.0 mEq/L that is persistent and refractory to correction], or history of long QT interval syndrome)
• Known active systemic hepatitis B, or C infection requiring therapy or known cirrhosis
• Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or pharmaceutical sponsor staff directly involved with this trial, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific subject
• 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 could interfere with the oral absorption or tolerance of pacritinib, including difficulty swallowing, are not eligible