What side effects are associated with this type of intervention?

Common treatments for AML, such as the combination of Venetoclax and Azacitidine, are associated with several side effects. These include hematologic toxicities like neutropenia, febrile neutropenia, thrombocytopenia, and anemia. Non-hematologic side effects can include gastrointestinal symptoms such as nausea, vomiting, constipation, and diarrhea, as well as infections, hypokalemia, and peripheral edema. The combination of these agents generally results in a higher incidence of these adverse events compared to monotherapy, but they are often manageable with supportive care.

What prior FDA approvals exist?

Venetoclax, a BCL-2 inhibitor, has been approved by the FDA for use in combination with low-dose cytarabine (LoDAC) and hypomethylating agents (HMAs) like Azacitidine for the treatment of newly diagnosed Acute Myeloid Leukemia (AML) in patients who are ineligible for intensive chemotherapy. Azacitidine, a hypomethylating agent, has also been approved for the treatment of AML, particularly in older adults or those unfit for intensive chemotherapy. These approvals highlight the FDA's recognition of the efficacy of combining Venetoclax with HMAs in improving clinical outcomes for AML patients.

What other types of research exist?

Promising alternatives to the combination of siremadlin, venetoclax, and azacitidine for AML patients include: 1) Azacitidine plus gilteritinib, which has shown a higher overall response rate compared to azacitidine plus placebo. 2) Decitabine with sapacitabine, which demonstrated similar outcomes to decitabine alone but with a slightly higher complete response rate. These combinations are noteworthy for their potential efficacy and manageable toxicity profiles.

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DNA Methyltransferase Inhibitor

Siremadlin + Venetoclax + Azacitidine for Acute Myeloid Leukemia

Phase 1

Waitlist Available

Research Sponsored by Novartis Pharmaceuticals

Eligibility Criteria Checklist

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

Must have

Participants must have specific ECOG performance status, WBC count, liver enzyme levels, and kidney function

Participants diagnosed with AML based on WHO 2016 classification who are ineligible for standard induction chemotherapy and have specific treatment history criteria

Must not have

Participants treated with FLT3 inhibitors

Participants who require treatment with substrates of CYP3A4/5 with a narrow therapeutic index

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests siremadlin with venetoclax and azacitidine in AML patients who can't have chemotherapy. It aims to see if this combination can improve treatment results without causing too many side effects. The trial was stopped by the sponsor for reasons unrelated to safety.

Who is the study for?

Adults with Acute Myeloid Leukemia (AML) who can't have standard chemotherapy are eligible. They must be over 18, not have achieved complete remission after 2-4 cycles of venetoclax plus azacitidine, or be newly diagnosed with a high genetic risk but without TP53 mutations. Exclusions include certain heart and lung conditions, poor kidney function, and those taking drugs that interact poorly with the trial medications.

What is being tested?

The study is testing siremadlin combined with venetoclax and azacitidine in AML patients ineligible for chemotherapy. It's designed to see if this combination helps when standard treatments aren't an option due to health risks or previous treatment failure.

What are the potential side effects?

Potential side effects may include nausea, vomiting, diarrhea, low blood counts leading to increased infection risk or bleeding problems, liver issues indicated by elevated enzymes, fatigue, and possible drug interactions affecting heart rhythm.

Eligibility Criteria

Inclusion Criteria

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

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My physical ability, blood cell count, liver, and kidney functions meet the study's requirements.

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I have AML and can't undergo standard chemotherapy due to my condition.

Exclusion Criteria

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

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I have been treated with FLT3 inhibitors.

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I need treatment with specific drugs that are sensitive to changes in their blood levels.

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I have previously been treated with MDM2-inhibitor therapy.

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I have a specific type of leukemia (AML-M3/APL) or AML because of Down's syndrome.

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My cancer has a TP53 mutation.

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My cancer has a del17p genetic mutation.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 3 years

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

Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)

Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)

Secondary study objectives

PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)

PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)

Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2)

+7 more

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

Group I: Arm 2: Newly diagnosed unfit adult participants with high-risk AMLExperimental Treatment3 Interventions

Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants).

Group II: Arm 1: Unfit adult participants with AML who responded sub-optimally to standard of careExperimental Treatment3 Interventions

Unfit adult participants with AML who responded sub-optimally to at least 2 and not more than 4 cycles ( 1 cycle=28 days) of first-line venetoclax plus azacitidine therapy

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

azacitidine

2005

Completed Phase 3

~1730

siremadlin

2022

Completed Phase 1

~20

venetoclax

2014

Completed Phase 2

~740

0 / 8Eligibility 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

The most common treatments for Acute Myeloid Leukemia (AML) include MDM2 inhibitors, BCL-2 inhibitors, and hypomethylating agents. MDM2 inhibitors, like Siremadlin, work by blocking the MDM2 protein, which normally inhibits the tumor suppressor p53; this allows p53 to induce cell death in cancer cells. BCL-2 inhibitors, such as Venetoclax, target the BCL-2 protein that prevents apoptosis, thereby promoting the death of leukemia cells. Hypomethylating agents like Azacitidine inhibit DNA methylation, leading to the reactivation of tumor suppressor genes and induction of cancer cell differentiation and death. These mechanisms are crucial for AML patients as they target the survival pathways of leukemia cells, offering a therapeutic strategy for those who are ineligible for intensive chemotherapy.