What is the mechanism of action of this treatment?

The most common treatments for Myelodysplastic Syndrome (MDS) include hypomethylation agents like decitabine and azacitidine, and BCL-2 inhibitors like venetoclax. Hypomethylation agents work by inhibiting DNA methyltransferase, leading to the reactivation of tumor suppressor genes and promoting normal cell differentiation and apoptosis of abnormal cells. BCL-2 inhibitors, such as venetoclax, target the BCL-2 protein, which is involved in preventing apoptosis. By inhibiting BCL-2, these drugs promote the death of cancer cells. These mechanisms are crucial for MDS patients as they help to reduce the number of abnormal cells in the bone marrow, improve blood cell production, and potentially extend survival.

What side effects are associated with this type of intervention?

The most common treatments for Myelodysplastic Syndrome (MDS) using hypomethylating agents like Decitabine and BCL-2 inhibitors like Venetoclax are associated with several side effects. Hypomethylating agents can cause cytopenias, gastrointestinal issues such as nausea, vomiting, and diarrhea, and fatigue. Venetoclax is known to cause prolonged cytopenias, febrile neutropenia, gastrointestinal effects, fatigue, and edema. Both treatments require careful monitoring due to their potential for significant hematologic toxicity.

What prior FDA approvals exist?

The FDA has approved several hypomethylating agents for the treatment of Myelodysplastic Syndrome (MDS), including Azacitidine and Decitabine. These agents work by promoting normal blood cell production and inducing the death of abnormal cells in the bone marrow. Venetoclax, a BCL-2 inhibitor, is another drug of interest, although it is primarily approved for certain types of leukemia. The combination of hypomethylating agents like Decitabine with Venetoclax is being studied for its potential efficacy in treating MDS, aiming to improve outcomes by leveraging the synergistic effects of these drug classes.

What other types of research exist?

Promising alternatives to Decitabine and Cedazuridine (ASTX727) with Venetoclax for Myelodysplastic Syndrome patients include: 1) Azacitidine plus Gilteritinib, which has shown a higher overall response rate compared to Azacitidine plus placebo. 2) Decitabine with Sapacitabine, which has demonstrated similar outcomes to Decitabine alone but with a slightly higher complete response rate.

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Hypomethylation Agent

Venetoclax + ASTX727 for Chronic Myelomonocytic Leukemia

Phase 2

Recruiting

Led By Rory M Shallis

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be older than 18 years old

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing if a combination of two drugs, ASTX727 and venetoclax, is more effective than ASTX727 alone in treating certain bone marrow cancers. It focuses on patients with CMML and MDS/MPN who have too many immature blood cells. ASTX727 helps produce normal blood cells and kills abnormal ones, while venetoclax blocks a protein that cancer cells need to survive. Venetoclax is an anticancer drug used to treat lymphomas and leukemias, but it has severe side effects.

Who is the study for?

Adults with chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm who haven't had specific previous treatments for these conditions. Participants must be able to swallow pills, have a certain level of heart and organ function, and not have uncontrolled illnesses. Pregnant women are excluded, and participants must agree to use contraception.

What is being tested?

The trial is testing if combining Venetoclax with ASTX727 (a mix of Decitabine and Cedazuridine) is more effective than ASTX727 alone in reducing symptoms of bone marrow cancer in patients with CMML or MDS/MPN with excess blasts.

What are the potential side effects?

Potential side effects include issues related to blood cell production, digestive system disturbances, liver enzyme changes, kidney function impairment, potential infection risk increase due to immune suppression, fatigue, and possible allergic reactions.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Complete response rate

Secondary study objectives

Incidence of adverse events

Overall survival (OS)

Progression-free survival (PFS)

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Active Control

Group I: Arm I (ASTX727, venetoclax)Experimental Treatment4 Interventions

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 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.

Group II: Arm II (ASTX727)Active Control4 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Venetoclax

2019

Completed Phase 3

~2200

Biospecimen Collection

2004

Completed Phase 3

~2020

Bone Marrow Biopsy

2021

Completed Phase 3

~230

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Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Myelodysplastic Syndrome (MDS) include hypomethylation agents like decitabine and azacitidine, and BCL-2 inhibitors like venetoclax. Hypomethylation agents work by inhibiting DNA methyltransferase, leading to the reactivation of tumor suppressor genes and promoting normal cell differentiation and apoptosis of abnormal cells. BCL-2 inhibitors, such as venetoclax, target the BCL-2 protein, which is involved in preventing apoptosis. By inhibiting BCL-2, these drugs promote the death of cancer cells. These mechanisms are crucial for MDS patients as they help to reduce the number of abnormal cells in the bone marrow, improve blood cell production, and potentially extend survival.