Clinical Trial Finder

Inclusion Criteria:

• - Ability to voluntarily provide written informed consent.

• - Documented diagnosis per World Health Organization (WHO) 2016 criteria of BCR-ABL negative myeloproliferative neoplasms (MPN).

• - Documented MPN transformation to accelerated phase (AP) or blast phase (BP) without prior blast reduction therapy for their AP/BP disease.

• - Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

• - Adequate organ function.

• - Must practice at least one reliable method of birth-control starting at least on cycle 1 day 1 until at least 90 days after the last dose of study drug.

• - Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to cycle 1 day 1.

Exclusion Criteria:

• - History of allogeneic stem cell transplant for MPN.

• - Previous treatment with venetoclax, navitoclax, azacytidine or other hypomethylating agents (HMA).

• - White blood cell count >25 x 10^9/L.

• - Current enrollment in another interventional study.

• - Presence of any active uncontrolled infection such as bacterial or fungal infections progressing despite adequate antimicrobial treatment.

• - Myocardial infarction in the preceding 3 months.

• - Active human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV) infection.

• - History of active malignancy in the previous 2 years.

• - Any psychiatric illness or social circumstances or significant co-morbid conditions that may compromise study participation.

• - Pregnant or breastfeeding women.

• - Patients with known central nervous system (CNS) involvement with acute myeloid leukemia (AML) or CNS extramedullary hematopoiesis.

• - Patients with t (15;17) - Patients who have received strong and/or moderate CYP3A inducers within 7 days prior to the initiation of study treatment.

• - Active COVID-19 infection.

• - History of prior blast-reduction therapy for AP/BP-MPN.

• - Preceding history MDS, chronic myelomonocytic leukemia (CMML), and other myelodysplastic syndromes (MDS)/MPN overlap syndromes.

All participants in this study will receive azacitidine and venetoclax. This study will be done in multiple stages: Safety Run-In Period

• - 7 participants will receive the study drugs to ensure that the combination is safe and tolerable.

Stage 1

• - About 15 participants will receive the study drugs and will be evaluated to see whether they respond to the study drugs.

Stage 2

• - If enough participants in Stage 1 respond to the study drugs, then Stage 2 will begin.

During this stage, an additional 25 participants will take part in the study to further see if participants respond to the study drugs.

Arms

Experimental: Azacitidine and Venetoclax

A treatment cycle is 28 days long. Azacitidine will be given by injection under the skin, once a day, for the first 6 days of every cycle. Venetoclax will be given orally, once a day, as follows at the discretion of their study doctors: Cycle 1: Day 1 - 100 mg Day 2 - 200 mg Days 3 to 28 - 400 mg Cycle 2: Participants with a response to the study drugs will continue taking 400 mg from Days 1 to 21, with no study drug from Days 22 to 28 during Cycle 2. Participants who have not yet responded to the study drugs will continue taking 400 mg from Days 1 to 28 during Cycle 2. Cycle 3 and subsequent cycles: Participants with a response to the study drugs will continue to take 400 mg from Days 1 to 21, with no study drug from Days 22 to 28. Participants whose disease has not worsened will continue taking 400 mg from Days 1 to 28. Participants have not responded to the study drugs will be withdrawn from the study.

Interventions

Drug: - Azacitidine

Azacitidine is a hypomethylating agent that works by activating certain genes in the body to help cells mature and to kill abnormal bone marrow cells.

Drug: - Venetoclax

Venetoclax is a drug that blocks a protein called B-cell lymphoma (BCL2) protein from working. BCL2 is a protein that helps control whether a cell lives or dies and is thought to help cancer cells to live. Blocking BCL2 is believed to help kill cancer cells.