What side effects are associated with this type of intervention?

Common treatments for Acute Myelogenous Leukemia (AML) include hypomethylating agents (HMAs) such as azacitidine and decitabine, often combined with other drugs like venetoclax or ivosidenib. Known side effects of these treatments include hematologic adverse events such as neutropenia, thrombocytopenia, and anemia. Non-hematologic side effects can include gastrointestinal issues like nausea and vomiting, as well as fatigue and infections such as pneumonia and sepsis. Specific to enzyme inhibitors like Pevonedistat, side effects may also include rash, fatigue, and vomiting.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myelogenous Leukemia (AML) that involve enzyme inhibition. Notably, venetoclax, an orally available BCL2 inhibitor, has been approved for use in combination with other agents like azacitidine or decitabine for the treatment of newly diagnosed AML in adults who are 75 years or older or who have comorbidities precluding the use of intensive induction chemotherapy. Additionally, ivosidenib, an IDH1 inhibitor, has been approved for the treatment of adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. These approvals highlight the FDA's recognition of enzyme inhibition as a viable therapeutic strategy for AML.

What other types of research exist?

Promising novel alternatives to Pevonedistat for AML patients include: 1) Venetoclax in combination with hypomethylating agents (HMAs) like azacitidine or decitabine, which has shown efficacy in both newly diagnosed and relapsed/refractory AML patients. 2) FLT3 inhibitors such as quizartinib, gilteritinib, and crenolanib, which are emerging as potent options for FLT3 mutant AML. 3) Ivosidenib for IDH1 mutations and enasidenib for IDH2 mutations, which are targeted therapies showing benefit in specific genetic subtypes of AML.

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Antimetabolite

Combination Chemotherapy for Acute Myeloid Leukemia or Myelodysplastic Syndrome

Phase 1

Waitlist Available

Led By Katherine G Tarlock

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

Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1

Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

Must not have

Patients who have a documented active uncontrolled infection

Patients who are receiving cyclosporine, tacrolimus or other systemic agents to prevent graft-versus-host disease post bone marrow transplant

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 1 year

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a combination of drugs to treat children with certain blood cancers that have not responded to other treatments. The drugs work together to block cancer cell growth and kill the cells in different ways.

Who is the study for?

This trial is for patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome. Participants must have recovered from previous cancer treatments, meet specific blood count criteria, and not have had certain therapies within specified time frames. They should not have prior exposure to pevonedistat and must be free of uncontrolled infections or severe liver impairment.

What is being tested?

The trial tests the effectiveness and side effects of a combination therapy including pevonedistat, azacitidine, fludarabine phosphate, and cytarabine in treating acute myeloid leukemia or myelodysplastic syndrome that has returned after treatment or hasn't responded to treatment.

What are the potential side effects?

Potential side effects may include reactions related to the immune system's response to the drugs, organ inflammation due to drug toxicity, fatigue from chemotherapy agents, digestive issues like nausea or diarrhea, blood disorders such as anemia or clotting problems.

Eligibility Criteria

Inclusion Criteria

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

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You must wait at least 21 days after receiving any antibody treatments before participating in the trial. Also, any side effects related to previous antibody treatments should have improved and be mild.

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You are currently taking chemotherapy or other cancer drugs that can lower your blood cell count.

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If you are taking hydroxyurea to reduce the number of blood cells, you must stop taking it at least 24 hours before starting the study treatment.

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You are able to perform daily activities and take care of yourself with little to moderate help.

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You have leukemia that has not responded to at least two rounds of chemotherapy, and your bone marrow still contains a high percentage of immature cells.

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You have advanced MDS (a type of blood cancer) that has progressed to AML and have not responded well to previous treatments.

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You have to wait at least two weeks after receiving any cancer treatment before you can participate in this trial, except for hydroxyurea. You must also have fully recovered from any side effects of the previous treatment.

Exclusion Criteria

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

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You have a documented and currently active infection that is not under control.

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You are taking medication that strongly affects the CYP3A4 enzyme and cannot stop taking it for 14 days before the study.

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You are currently taking part in another research study.

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You cannot be taking any cancer drugs, except for hydroxyurea which can be taken up to 24 hours before starting the study treatment.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 1 year

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 1 year

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 1 year for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Area Under the Plasma Concentration Versus Time Curve of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

Elimination Half-life of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

Maximum Concentration of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

+4 more

Secondary study objectives

Number of Participants With Antitumor Activity of MLN4924 (Pevonedistat)

Other study objectives

Messenger Ribonucleic Acid (mRNA) Transcript Levels of MLN4924 (Pevonedistat) Added to the 3-drug Backbone of Azacitidine (Aza), Fludarabine, and Cytarabine Re-induction for Pediatric Patients With Recurrent/Refractory AML and MDS

Side effects data

From 2024 Phase 3 trial • 454 Patients • NCT03268954

41%

Constipation

37%

Anaemia

35%

Neutropenia

34%

Thrombocytopenia

29%

Nausea

25%

Pyrexia

23%

Diarrhoea

21%

Vomiting

19%

Asthenia

16%

Febrile neutropenia

15%

Fatigue

14%

Oedema peripheral

11%

Cough

11%

Decreased appetite

11%

Arthralgia

11%

Dizziness

11%

Pneumonia

10%

Platelet count decreased

10%

Epistaxis

10%

Insomnia

10%

Pain in extremity

10%

Dyspnoea

Hypokalaemia

Upper respiratory tract infection

Headache

Injection site erythema

Back pain

Neutrophil count decreased

Urinary tract infection

Hyperuricaemia

Abdominal pain

Oropharyngeal pain

Blood creatinine increased

Hypertension

Pruritus

Leukopenia

Sepsis

Alanine aminotransferase increased

Aspartate aminotransferase increased

Hypomagnesaemia

Abdominal pain upper

White blood cell count decreased

Fall

Hypotension

Myalgia

Abnormal loss of weight

Injection site pain

Contusion

Lower respiratory tract infection

Septic shock

Haemorrhoids

Hypophosphataemia

Stomatitis

Blood bilirubin increased

Musculoskeletal pain

COVID-19 pneumonia

Infection

Respiratory tract infection

General physical health deterioration

Multiple organ dysfunction syndrome

Respiratory failure

Acute respiratory failure

Organising pneumonia

Gastrointestinal haemorrhage

Cardiac failure

COVID-19

Cerebrovascular accident

Haemorrhage intracranial

Myocardial infarction

Acute myeloid leukaemia

Malignant melanoma

Soft tissue necrosis

Intestinal obstruction

Pleural effusion

Fluid overload

100%

80%

60%

40%

20%

Study treatment Arm

Azacitidine 75 mg/m^2

Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2

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 (cytarabine, azacitidine, pevonedistat, fludarabine)Experimental Treatment6 Interventions

Patients receive cytarabine intrathecally on day 0 at least 24 hours prior to the start of each cycle. Patients then receive azacitidine IV over 15 minutes QD on days 1-5, pevonedistat IV over 60 minutes on days 1, 3, and 5, and fludarabine phosphate IV over 30 minutes QD and cytarabine IV over 1-3 hours QD on days 6-10. Patients with CNS2 or CNS3 receive cytarabine intrathecally or methotrexate intrathecally, hydrocortisone intrathecally, and cytarabine intrathecally on days 8 and 11-34. Cycles continue for 35 days in the absence of disease progression or unacceptable toxicity. Patients with stable or greater with non-hematologic toxicities probably or definitely related to pevonedistat may receive an additional cycle of treatment.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Azacitidine

2012

Completed Phase 3

~1440

Fludarabine Phosphate

1997

Completed Phase 3

~2390

Methotrexate

2019

Completed Phase 4

~4400

Therapeutic Hydrocortisone

2012

Completed Phase 3

~560

Cytarabine

2016

Completed Phase 3

~3330

Pevonedistat

2021

Completed Phase 3

~770

0 / 19Eligibility 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 (HMAs) like azacitidine and decitabine, which work by inhibiting DNA methylation, leading to the reactivation of tumor suppressor genes and induction of cancer cell death. Venetoclax, a BCL-2 inhibitor, promotes apoptosis in leukemia cells by disrupting their survival mechanisms. Pevonedistat, an enzyme inhibitor, targets the NEDD8-activating enzyme, disrupting protein degradation pathways essential for cancer cell survival. These treatments are crucial for AML patients, especially those unfit for intensive chemotherapy, as they offer less aggressive yet effective therapeutic options.

Molecular targeting in acute myeloid leukemia.