What side effects are associated with this type of intervention?

Common treatments for AML, such as hypomethylating agents (HMAs) like decitabine and azacitidine, often cause side effects including cytopenias, febrile neutropenia, and neutropenic fever, which frequently necessitate hospitalization. Kinase inhibitors like entrectinib can cause side effects such as differentiation syndrome, prolonged QTc interval, anemia, thrombocytopenia, and leukocytosis. These treatments require careful monitoring and dose adjustments to manage these adverse effects.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myelogenous Leukemia (AML) that are similar to the combination of ASTX727 and Entrectinib. Hypomethylating agents such as azacitidine and decitabine have been approved for the treatment of AML, particularly in patients who are not candidates for intensive chemotherapy. These agents work by modifying the DNA methylation process, thereby promoting normal cell function and apoptosis of cancer cells. Additionally, kinase inhibitors like midostaurin and gilteritinib have been approved for AML with specific genetic mutations (FLT3 mutations), targeting abnormal proteins that drive cancer cell proliferation. These approvals provide a foundation for exploring new combinations like ASTX727 and Entrectinib in clinical trials.

What other types of research exist?

Promising novel alternatives for AML treatment include: 1) Venetoclax in combination with hypomethylating agents (HMAs) like azacitidine or decitabine, which has shown improved outcomes in clinical trials. 2) Ivosidenib, particularly for patients with IDH1 mutations, when combined with HMAs. 3) Enasidenib for patients with IDH2 mutations, which has demonstrated efficacy in relapsed or refractory AML. These alternatives have shown clinical benefits and are likely to be relevant treatment options in 2024.

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Cytidine Deaminase Inhibitor

Entrectinib + ASTX727 for Acute Myeloid Leukemia

Q: What is the mechanism of action of this treatment?

Common treatments for Acute Myelogenous Leukemia (AML) include hypomethylating agents, cytidine deaminase inhibitors, and kinase inhibitors. Hypomethylating agents like decitabine inhibit DNA methylation, reactivating tumor suppressor genes and inducing cancer cell death. Cytidine deaminase inhibitors, such as cedazuridine, prevent the breakdown of hypomethylating agents, enhancing their effectiveness. Kinase inhibitors like entrectinib block abnormal proteins that signal cancer cells to multiply, slowing or stopping cancer spread. These treatments are crucial for AML patients as they target the genetic and molecular abnormalities driving the disease, offering a more tailored and potentially effective approach.

Phase 1

Recruiting

Led By Ronan T Swords, M.D.

Research Sponsored by OHSU Knight Cancer Institute

Eligibility Criteria Checklist

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

Must have

Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 × ULN

Documented TP53 mutation as seen on standard diagnostics in AML

Must not have

Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent or who have agent-related toxicity that has not resolved to grade 1 or less. If the half-life of an investigational agent is unknown, patients must wait 1 week after discontinuing it before receiving the first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA)

Participants with prior documented history of malabsorption syndrome (e.g., short gut syndrome) that might limit the bioavailability of study medications will be excluded

Timeline

Screening 3 weeks

Treatment Varies

Follow Up from first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months

Awards & highlights

No Placebo-Only Group

All Individual Drugs Already Approved

Summary

This trial tests a combination of two medications for patients with a tough-to-treat type of leukemia. One drug stops cancer cells from growing, while the other helps make healthy blood cells and kills bad ones. The goal is to find the best dose and see if this combination is safe and effective.

Who is the study for?

Adults with relapsed/refractory AML and a TP53 mutation can join this trial. They must understand the study, be able to take oral meds, have decent organ function, and use contraception. Excluded are those with certain leukemia types, active infections like HIV or hepatitis B/C, uncontrolled diseases, recent investigational drugs usage or conditions affecting drug absorption.

What is being tested?

The trial is testing entrectinib combined with ASTX727 (cedazuridine plus decitabine) for safety and effectiveness in AML patients. Entrectinib blocks cancer cell growth signals; cedazuridine increases decitabine's availability which helps produce normal blood cells and kills abnormal ones.

What are the potential side effects?

Potential side effects include reactions related to immune system activation such as inflammation of organs, infusion-related symptoms, fatigue from treatment burden on the body, digestive issues due to medication impact on gut health, possible blood disorders from bone marrow activity changes.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidney function is within the required range.

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My AML has a confirmed TP53 mutation.

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My AML has returned or didn't respond to treatment, with at least 20% cancer cells in my blood or bone marrow.

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I can take care of myself but might not be able to do heavy physical work.

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I am 18 years old or older.

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I can take medicine by mouth.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't taken any experimental drugs recently or still have side effects from one.

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I do not have a history of conditions like short gut syndrome that affect medication absorption.

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I do not have any severe heart problems or other serious illnesses that are not under control.

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I have a blood clotting disorder with active bleeding or signs of clotting.

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I have been diagnosed with a specific type of leukemia called M3.

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I have AML affecting my blood or bone marrow.

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My acute myeloid leukemia has spread to my brain or spinal cord.

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I do not have active HIV, hepatitis B, or hepatitis C.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ from first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~from first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and from first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Incidence of dose limiting toxicities (DLTs)

Secondary study objectives

Clinical benefit rate (CBR)

Composite complete remission (CCR) rate

Duration of response (DOR)

+5 more

Other study objectives

Pyruvate Kinase

Genomic analysis

NTRK gene expression

+4 more

Awards & Highlights

No Placebo-Only Group

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

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (ASTX727, entrectinib)Experimental Treatment3 Interventions

Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Entrectinib

FDA approved

0 / 14Eligibility criteria met

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

Common treatments for Acute Myelogenous Leukemia (AML) include hypomethylating agents, cytidine deaminase inhibitors, and kinase inhibitors. Hypomethylating agents like decitabine inhibit DNA methylation, reactivating tumor suppressor genes and inducing cancer cell death. Cytidine deaminase inhibitors, such as cedazuridine, prevent the breakdown of hypomethylating agents, enhancing their effectiveness. Kinase inhibitors like entrectinib block abnormal proteins that signal cancer cells to multiply, slowing or stopping cancer spread. These treatments are crucial for AML patients as they target the genetic and molecular abnormalities driving the disease, offering a more tailored and potentially effective approach.

Molecular targeting in acute myeloid leukemia.