Venetoclax in Combination With ASTX727 for the Treatment of Chronic Myelomonocytic Leukemia and Other Myelodysplastic Syndrome/Myeloproliferative Neoplasm

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Description

This phase II trial tests whether decitabine and cedazuridine (ASTX727) in combination with venetoclax work better than ASTX727 alone at decreasing symptoms of bone marrow cancer in patients with chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) with excess blasts. Blasts are immature blood cells. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. 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. The combination of ASTX727 and venetoclax may be more effective in reducing the cancer signs and symptoms in patients with CMML, or MDS/MPN with excess blasts.

Study Overview

Start Date
June 27, 2023
Completion Date
August 31, 2025
Enrollment
132
Date Posted
November 1, 2022
Accepts Healthy Volunteers?
No
Gender
All

Locations

Full Address
UC Irvine Health Cancer Center-Newport
Costa Mesa, California 92627, United States

UCI Health Laguna Hills
Laguna Hills, California 92653, United States

Los Angeles General Medical Center
Los Angeles, California 90033, United States

USC / Norris Comprehensive Cancer Center
Los Angeles, California 90033, United States

UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California 92868, United States

University of California Davis Comprehensive Cancer Center
Sacramento, California 95817, United States

Northwestern University
Chicago, Illinois 60611, United States

University of Chicago Comprehensive Cancer Center
Chicago, Illinois 60637, United States

UC Comprehensive Cancer Center at Silver Cross
New Lenox, Illinois 60451, United States

University of Chicago Medicine-Orland Park
Orland Park, Illinois 60462, United States

University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas 66205, United States

Montefiore Medical Center-Einstein Campus
Bronx, New York 10461, United States

Montefiore Medical Center-Weiler Hospital
Bronx, New York 10461, United States

Montefiore Medical Center - Moses Campus
Bronx, New York 10467, United States

UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina 27599, United States

Wake Forest University Health Sciences
Winston-Salem, North Carolina 27157, United States

University of Cincinnati Cancer Center-UC Medical Center
Cincinnati, Ohio 45219, United States

Ohio State University Comprehensive Cancer Center
Columbus, Ohio 43210, United States

University of Cincinnati Cancer Center-West Chester
West Chester, Ohio 45069, United States

University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104, United States

University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania 15232, United States

Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah 84112, United States

University of Virginia Cancer Center
Charlottesville, Virginia 22908, United States

Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia 23298, United States

University Health Network-Princess Margaret Hospital
Toronto, Ontario M5G 2M9, Canada

Eligibility

Minimum Age (years)
18
Eligibility Criteria
Inclusion Criteria:

A diagnosis of MDS/MPN with >= 5% marrow blasts. Hydroxyurea may be used to control counts up until the start of therapy
White blood cell (WBC) < 10,000/mm^3. Treatment with hydroxyurea is permitted to lower the WBC to reach this criterion. The WBC should be determined >= 24 hours after the last dose of hydroxyurea
Age >= 18 years. Because no dosing or adverse event data are currently available on the use of ASTX727 in combination with venetoclax in patients < 18 years of age, children are excluded from this study
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless considered due to Gilbert's syndrome)
Aspartate aminotransferase (AST) serum aspartate aminotransferase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 3.0 x institutional ULN OR =< 5.0 x institutional ULN for patients with liver metastases
Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Hormonal therapy for prior or concurrent malignancy is allowed
Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) and/or family member available will also be eligible
Ability to swallow pills

Exclusion Criteria:

Patients with need for emergent disease-directed therapy excluding hydroxyurea
Previous MDS/MPN-directed therapy, AML or MDS-directed therapy including lenalidomide and hypomethylating agent (HMAs) such as decitabine or azacitidine, excluding hydroxyurea. Prior use of erythropoietin stimulating agents (ESA) and thrombopoietic agents is allowed, but must be discontinued 4 weeks prior to study treatment
Patients currently or previously receiving an investigational agent or device within 4 weeks of the first dose of treatment
Patients with symptomatic uncontrolled central nervous system (CNS) disease. Imaging to confirm the absence of brain metastases is not required. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days
Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days prior to the initiation of study treatment and are unwilling to discontinue consumption of these throughout the receipt of study drug
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ASTX727 or venetoclax
Patients with uncontrolled intercurrent illness (e.g. requiring intravenous therapy) at the discretion of the investigator

Pregnant women are excluded from this study because venetoclax and ASTX727 have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, breastfeeding should be discontinued if the mother is treated with venetoclax. These potential risks may also apply to other agents used in this study. Patients must be post-menopausal or with evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on Day 1.

Post-menopausal is defined as:

Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for women under 50 years of age
Radiation-induced oophorectomy with last menses > 1 year ago
Chemotherapy-induced menopause with > 1 year interval since last menses
Surgical sterilization (bilateral oophorectomy or hysterectomy)
Women of child-bearing potential must agree to use adequate contraception (hormonal birth control or abstinence) prior to study entry and for the duration of study participation, and for 6 months following completion of study treatment. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception (latex or synthetic condom or abstinence) prior to the study, for the duration of study participation, and 3 months after completion of venetoclax and ASTX727 administration
Patients with any other medical condition for which the expected survival is below 12 months
Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or assessment of the investigational regimen
Patients with active infection at the time of study entry

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Other Details

FDA Regulated Drug?
Yes
FDA Regulated Device?
No
Detailed Description
PRIMARY OBJECTIVE:

I. To evaluate the complete remission rates of ASTX727 and ASTX727 plus venetoclax in subjects with chronic myelomonocytic leukemia (CMML) and non-CMML myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with excess (>= 5%) blasts.

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (complete response [CR] + partial response [PR] + marrow response with erythroid response) of ASTX727 versus ASTX727 + venetoclax in this patient population.

II. To determine the overall survival, progression-free survival, allogeneic hematopoietic stem cell transplantation rate, clearance of the malignant clone, clonality at time of hematologic remission, number of red cell and platelet transfusions required and toxicity of ASTX727 versus ASTX727 + venetoclax.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I (COMBINATION THERAPY): Patients receive ASTX727 orally (PO) daily (QD) for 5 consecutive days starting on day 3 of treatment cycle 1; followed by day 1 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive venetoclax PO QD on days 1 through 14 of each treatment cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsies, and collection of blood and buccal samples throughout the study.

ARM II (MONO THERAPY): Patients receive ASTX727 PO QD for 5 consecutive days starting on day 3 of treatment cycle 1; followed by day 1 of each subsequent cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who do not have response to treatment may cross over to Arm I. Patients also undergo bone marrow biopsies, and collection of blood and buccal samples throughout the study.

After completion of study treatment, patients are followed for 2 years.
NCTid (if applicable)
NCT05600894