Study of Venetoclax and Azacitidine in Advanced BCR-ABL Negative Myeloproliferative Neoplasms

Study Overview
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Brief Summary
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The purpose of this research study is to look at how safe and useful a drug called azacitidine in combination with a drug called venetoclax, is in people with accelerated or blast phase BRC-ABL negative myeloproliferative neoplasms.

Detailed Description
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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.

Official Title
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Venetoclax and Azacitidine Combination Therapy for Patients With Accelerated or Blast Phase BCR-ABL Negative Myeloproliferative Neoplasm (VAAMP)

Conditions
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Myeloproliferative Neoplasm

Intervention / Treatment
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* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine and Venetoclax<br>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. | Drug: Azacitidine<br>* 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.<br>Drug: Venetoclax<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants achieving complete remission (CR). |  | 3 years | 
| Proportion of participants achieving complete remission with incomplete hematologic recovery (CRi). |  | 3 years | 
| Proportion of participants achieving reversion to chronic myeloproliferative neoplasm (CMPN). |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average number of days from the first dose of azacytidine and venetoclax to the date of death. |  | 3 years | 
| Average number of days from CR until relapse. |  | 3 years | 
| Average number of days from CRi until relapse. |  | 3 years | 
| Average number of days from CMPN until relapse. |  | 3 years | 
| The proportion of patients proceeding to allogeneic stem cell transplantation in those eligible for transplantation. |  | 3 years |