What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents like decitabine and low-dose cytarabine (LoDAC), often combined with other agents such as venetoclax or glasdegib. Decitabine is associated with cytopenias, febrile neutropenia, and the need for hospitalization due to neutropenic fever. LoDAC combined with venetoclax or glasdegib can lead to similar side effects, including neutropenia and febrile neutropenia. Enzyme inhibition treatments like M3814, when combined with chemotherapy agents such as mitoxantrone, etoposide, and cytarabine, may also cause gastrointestinal issues, rash, fatigue, and vomiting. Overall, neutropenia and infection-related complications are common across these treatments.

What prior FDA approvals exist?

Several FDA-approved treatments for Acute Myeloid Leukemia (AML) involve enzyme inhibition. Venetoclax, an orally available BCL2 inhibitor, is approved for use in combination with hypomethylating agents like azacitidine or decitabine. Ivosidenib, an IDH1 inhibitor, is approved for patients with IDH1-mutated AML. Additionally, gilteritinib, an FLT3 inhibitor, is approved for relapsed or refractory AML with FLT3 mutations. These treatments target specific enzymes involved in the growth and survival of AML cells, similar to the investigational agent M3814 being studied for its enzyme inhibition properties.

What other types of research exist?

Promising novel alternatives to M3814 for AML patients include hypomethylating agents (HMAs) such as azacitidine and decitabine, which have shown comparable efficacy and are well-tolerated. Additionally, targeted therapies like ivosidenib for mutant IDH1 and enasidenib for mutant IDH2 are also promising options. These treatments have demonstrated effectiveness in clinical settings and offer alternative mechanisms of action for managing AML.

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Anti-metabolites

M3814 + Chemotherapy for Acute Myeloid Leukemia

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

Common treatments for Acute Myeloid Leukemia (AML) include chemotherapy, targeted therapy, and enzyme inhibitors. Chemotherapy drugs like cytarabine and daunorubicin work by killing rapidly dividing cells, which include cancer cells. Targeted therapies, such as FLT3 inhibitors, specifically target mutations in cancer cells, thereby reducing damage to normal cells. Enzyme inhibitors, like the investigational drug M3814, block specific enzymes necessary for cancer cell growth and survival. This is crucial for AML patients as it offers a more precise treatment approach, potentially reducing side effects and improving outcomes by directly targeting the molecular abnormalities driving the leukemia.

Phase 1

Recruiting

Led By Brian A Jonas

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

- Refractory: no CR or CRi after one or more cycles of induction. Induction cycles include regimens with the intent to achieve remission and can include high intensity and/or low intensity regimens

Patients must be medically eligible to receive MEC, including acceptable pre-study cardiac function (left ventricular ejection fraction of >= 45%) and lifetime anthracycline exposure (=< 360 mg/m^2 daunorubicin equivalents)

Must not have

Patients must not have documented active central nervous system (CNS) involvement by leukemia. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events (AEs)

Patients must not have known significant cardiopulmonary disease defined as:

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug called M3814 combined with three chemotherapy drugs to treat patients with a difficult type of leukemia. The new drug blocks cancer cell growth, and the chemotherapy drugs kill or stop the cancer cells.

Who is the study for?

Adults (18+) with acute myeloid leukemia that's relapsed or hasn't responded to treatment, without severe allergies or conditions. They must have acceptable organ function and performance status, no active central nervous system involvement by leukemia, not be on certain medications affecting enzyme CYP3A4/5, and agree to use contraception.

What is being tested?

The trial is testing the effectiveness of adding M3814 to standard chemotherapy drugs (mitoxantrone, etoposide phosphate, cytarabine) in patients with relapsed/refractory acute myeloid leukemia. It aims to find the best dose of M3814 and monitor its side effects when combined with these chemotherapies.

What are the potential side effects?

Potential side effects include reactions related to cell growth inhibition by M3814 and typical chemotherapy effects like nausea, fatigue, hair loss except alopecia resolved to grade <=1 per NCI criteria. Organ inflammation and blood disorders may also occur.

Eligibility Criteria

Inclusion Criteria

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

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My cancer did not fully respond to initial treatment cycles aimed at remission.

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My heart is strong enough for treatment, and I haven't had too much of a certain cancer drug.

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All my side effects from previous cancer treatments, except hair loss, are mild or gone.

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I am 18 years old or older.

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I am mostly self-sufficient and can carry out daily activities.

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I have been diagnosed with AML, not including the type known as APL.

Exclusion Criteria

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

Select...

I do not have leukemia affecting my brain.

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I do not have serious heart or lung disease.

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I haven't taken any experimental or new treatments for my leukemia in the last 14 days or less, except for treatments to control white blood cell counts.

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I haven't taken strong medication affecting liver enzymes for at least 3 weeks.

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I have never been treated with MEC.

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I am not taking sorivudine or similar drugs.

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I do not have severe heart failure.

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I am not taking medications that affect my heart's electrical cycle.

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I haven't had a live vaccine or an active infection in the last 30 days.

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My heart's electrical cycle is longer than normal.

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I have unstable chest pain.

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

Incidence of adverse events

Secondary study objectives

Duration of CR/CRi

Event-free survival

Overall response rate

+2 more

Other study objectives

Effect of cytogenetic and molecular abnormalities

Pharmacodynamic effects of M3814 in combination with MEC

Rate of allogeneic hematopoietic cell transplantation (HCT)

+1 more

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (peposertib, mitoxantrone, etoposide, cytarabine)Experimental Treatment8 Interventions

Patients receive peposertib PO BID on days 2-21, mitoxantrone IV over 15 minutes, etoposide IV over 60 minutes and cytarabine IV over 60 minutes on days 1-5 in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo ECHO and MUGA during baseline, and blood collection and bone marrow biopsy throughout the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Multigated Acquisition Scan

2015

Completed Phase 3

~270

Biospecimen Collection

2004

Completed Phase 3

~2020

Bone Marrow Biopsy

2021

Completed Phase 3

~230

Cytarabine

2016

Completed Phase 3

~3330

Etoposide Phosphate

2011

Completed Phase 2

~160

Mitoxantrone Hydrochloride

2016

Completed Phase 3

~650

Peposertib

2021

Completed Phase 1

~20

0 / 17Eligibility 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 Myeloid Leukemia (AML) include chemotherapy, targeted therapy, and enzyme inhibitors. Chemotherapy drugs like cytarabine and daunorubicin work by killing rapidly dividing cells, which include cancer cells. Targeted therapies, such as FLT3 inhibitors, specifically target mutations in cancer cells, thereby reducing damage to normal cells. Enzyme inhibitors, like the investigational drug M3814, block specific enzymes necessary for cancer cell growth and survival. This is crucial for AML patients as it offers a more precise treatment approach, potentially reducing side effects and improving outcomes by directly targeting the molecular abnormalities driving the leukemia.

Progress in the problem of relapsed or refractory acute myeloid leukemia.Molecular targeting in acute myeloid leukemia.Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia.