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
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.
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.
Single group
Pacritinib
DrugSubjects will be dosed until MTD is reached
Venetoclax
DrugGiven PO
Azacitidine
DrugGiven SC or IV
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Computed Tomography
Procedure/SurgeryUndergo CT
Bone Marrow Aspiration
Procedure/SurgeryUndergo bone marrrow aspiration
To determine the maximum tolerated dose (MTD) of the treatment regimen.
WIll be measured by assessing DLTS in a Bayesian optimal interval )BOIN design to determine the MTD
Incidence of adverse events (AEs)
Will be assessed and graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, including but not limited to AEs, serious adverse events, DLTs, and clinical laboratory and electrocardiogram abnormalities.
Percentage of Complete Response
Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.
Complete response with incomplete hematologic recovery rate
As defined by ELN 2022 AML response criteria. Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.
Complete response with partial hematologic recovery rate
As defined by ELN 2022 AML response criteria. Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.
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