Phase I Trial of Pacritinib in Combination With Venetoclax and Azacitidine for the Treatment of Accelerated and Blast Phase Myeloproliferative Neoplasms

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

Study Overview

• Status: Not yet recruiting
• Conditions: Myeloproliferative Neoplasm
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Drug: Azacitidine; Procedure: Computed Tomography; Drug: Venetoclax; Drug: Pacritinib; Procedure: Bone Marrow Aspiration

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: ASK ROSWELL; Phone Number: 1-800-767-9355; Email: AskRoswell@roswellpark.org

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
      • Contact: ASK Roswell; Phone Number: 800-767-9355; Email: AskRoswell@roswellpark.org
      • Principal Investigator: Steven Green, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment Arm 1; Pacritinib in combination with venetoclax and azacitidne. Dose will increase until side effects occur or maximum tolerated dose is reached. Additionally, patients undergo MRI or CT as well as bone marrow aspiration and biopsy throughout the trial.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Drug: Azacitidine; Given SC or IV; Other Names: 320-67-2; Procedure: Computed Tomography; Undergo CT; Other Names: CAT Scan; Drug: Venetoclax; Given PO; Other Names: 1257044-40-8; Drug: Pacritinib; Subjects will be dosed until MTD is reached; Other Names: SB-1518; 937272-79-2; Procedure: Bone Marrow Aspiration; Undergo bone marrrow aspiration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	At the end of Cycle 1 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 30 days post treatment
Percentage of Complete Response	Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	24 months
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.	Up to 1 year post start of treatment
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.	UP to 1 year post start of treatment
Complete Response without evidence of measurable residual disease rate	Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	UP to 1 year post start of treatment
Morphological leukemia-free state rate	Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	Up to 1 year post start of treatment
Partial remission Rate	Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	Up to 1 year post start of treatment
Complete molecular response rate	Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	Up to 1 year post start of treatment
Complete cytogenetic response rate	As defined by Post-MPN AML Consortium 2012 criteria. Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals	Up to 1 year post start of treatment
Acute leukemia response - complete rate	As defined by Post-MPN AML Consortium 2012 criteria. Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals.	Up to 1 year post start of treatment
Acute leukemia - partial rate	As defined by Post-MPN AML Consortium 2012 criteria. Will be summarized using frequencies and relative frequencies. Response rates will be presented along with the corresponding 90% confidence intervals	Up to 1 year post start of treatment
Change in Spleen volume	summarized by MRI or CT	fAt baseline to week 12 and 24

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Steven Green, MD, Roswell Park Comprehensive Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: June 30, 2026
• First Posted (Actual): July 1, 2026

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 30, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Bone Marrow Diseases; Hemic and Lymphatic Diseases; Myeloproliferative Disorders; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Chemistry Techniques, Analytical; Spectrum Analysis; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; Magnetic Resonance Spectroscopy; venetoclax; 11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
• Other Study ID Numbers: I-3685225

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No