Pevonedistat + Decitabine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Hydroxyurea

Must not be taking: CYP3A4/5 inducers

Disqualifiers: Active malignancies, Cardiopulmonary disease, Infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: Up to 24 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the combination of pevonedistat (MLN4924) and decitabine (Dacogen) to determine the optimal dose and assess side effects in treating acute myeloid leukemia (AML). These drugs may inhibit cancer cell growth by blocking essential enzymes. The trial targets patients with AML who have relapsed, have high-risk disease, or cannot undergo standard chemotherapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this potentially groundbreaking therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, any prior chemotherapy must be completed at least 2 weeks before starting the study treatment, and certain medications like hydroxyurea are allowed only during the first cycle. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that pevonedistat, when used alone, is generally safe for patients with conditions like multiple myeloma and lymphoma, meaning most people did not experience serious side effects. In studies where pevonedistat was used by itself, early evidence suggests it was manageable for patients.

Decitabine is an approved treatment for some blood cancers, so its safety is well-known, although it can still cause side effects like any medication.

Researchers are testing the combination of pevonedistat and decitabine to see how they work together in treating high-risk acute myeloid leukemia. Since this is an early study, researchers are still learning how well patients handle the combination. The trial will determine if the combination causes any unexpected side effects or if it is well-tolerated, based on existing knowledge of each drug separately. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about pevonedistat combined with decitabine for treating Acute Myeloid Leukemia (AML) because it offers a novel approach to tackling this aggressive cancer. Most current AML treatments focus on chemotherapy to stop cancer cells from growing. However, pevonedistat works differently by inhibiting a protein called NEDD8-activating enzyme, which is crucial for cancer cell survival. This unique mechanism can potentially enhance the effectiveness of decitabine, a drug already used in AML treatment, and might offer hope for better outcomes in patients resistant to standard chemotherapy.

What evidence suggests that pevonedistat and decitabine could be effective for acute myeloid leukemia?

Research has shown that combining pevonedistat with decitabine may help treat acute myeloid leukemia (AML). In this trial, participants will receive both drugs. Pevonedistat blocks an enzyme that cancer cells need to grow. Studies have found that pevonedistat can be effective on its own for some AML patients. Decitabine, already used to treat AML, interferes with DNA to stop cancer cells from multiplying. Together, these drugs might enhance each other's effects, possibly leading to better results for patients. Early evidence suggests this combination could offer a new approach for treating high-risk AML. ^{1 2 6 7 8}

Who Is on the Research Team?

Guido Marcucci

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults aged 60 or older with high-risk acute myeloid leukemia (AML), either newly diagnosed, untreated and not candidates for standard chemotherapy, or those with relapsed/refractory disease. It includes younger AML patients unfit for stem cell transplant. Participants must have a life expectancy over 6 months, be able to perform daily activities (ECOG <=2), and use effective contraception if of childbearing potential.

Inclusion Criteria

You are 60 years or older and your disease has come back or is not responding to treatment.

If you have cancer cells that have spread outside of your bone marrow, you may still be eligible for the study if you meet other criteria.

You have other medical conditions, but they are not expected to shorten your life expectancy within the next six months.

Exclusion Criteria

You do not have any other active cancer except for certain types that have been cured or treated a long time ago.

You have a serious medical or mental health condition that could affect your ability to participate in the study.

You have not taken any experimental medications within the 2 weeks before starting the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5 and decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unexpected toxicity.

Up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Monthly for 1 year, bi-monthly for another year

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Pevonedistat

Trial Overview The study is testing the combination of two drugs: pevonedistat and decitabine, to determine their safety and optimal dosages in treating high-risk AML. The goal is to see if these drugs can halt cancer growth by inhibiting enzymes necessary for cell proliferation.

How Is the Trial Designed?

Group I: Treatment (pevonedistat, decitabine) Experimental Treatment 4 Interventions

Patients receive pevonedistat IV over 1 hour on days 1, 3, and 5 and decitabine IV over 1 hour on days 1-5 and 8-12. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unexpected toxicity.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03009240

Pevonedistat and Decitabine in Treating Patients With High ... This phase I trial studies the side effects and best dose of pevonedistat when given together with decitabine in treating patients with high risk acute ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5909884/

Pevonedistat, a first-in-class NEDD8-activating enzyme ... Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia ( ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9310330/

The development of pevonedistat in myelodysplastic ... In this review, we summarize the preclinical and clinical rationale for pevonedistat in MDS and AML, review the clinical data of this agent alone and in ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/22/4/847/251332/Phase-I-Study-of-the-Investigational-NEDD8

Phase I Study of the Investigational NEDD8-Activating ... Increased transaminases were among the common AEs in other phase I studies of pevonedistat in myeloma and lymphoma (36), and acute myeloid leukemia (AML; 23% of ...

5. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/1380/427290/Pevonedistat-a-Nedd-8-Activating-Enzyme-Inhibitor

Pevonedistat, a Nedd-8 Activating Enzyme Inhibitor ... Introduction: Venetoclax (VEN), a selective BCL-2 inhibitor, has yielded exceptional response rates in patients with acute myeloid leukemia ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119427286

The Novel, Investigational NEDD8-Activating Enzyme ... Acute Myeloid Leukemia ... Updated efficacy and safety data will be presented, together with data on MLN4924 pharmacokinetics and pharmacodynamics ...

7. aacrjournals.org aacrjournals.org/clincancerres/article/22/1/34/248589/Phase-I-Study-of-the-Novel-Investigational-NEDD8

Phase I Study of the Novel Investigational NEDD8-Activating ... The safety profile of single-agent pevonedistat in patients with multiple myeloma and lymphoma was generally tolerable, and there was preliminary evidence that ...

8. journals.sagepub.com journals.sagepub.com/doi/10.1177/20406207221112899

The development of pevonedistat in myelodysplastic ... In this review, we summarize the preclinical and clinical rationale for pevonedistat in MDS and AML, review the clinical data of this agent ...