Pevonedistat + Venetoclax + Azacitidine for Acute Myeloid Leukemia

(PEVENAZA Trial)

No longer recruiting at 72 trial locations

Overseen By Takeda Study Registration Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Takeda

Must not be taking: Hypomethylating agents

Disqualifiers: BCR-ABL1 translocation, CNS involvement, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug combination for adults with acute myeloid leukemia (AML) who cannot receive intensive chemotherapy. Participants will receive either a mix of three drugs—pevonedistat (an experimental treatment), venetoclax, and azacitidine—or just venetoclax and azacitidine. The goal is to determine if adding pevonedistat improves treatment outcomes. This trial suits those recently diagnosed with AML who cannot handle strong chemotherapy due to other health issues. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor to get specific guidance based on your situation.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of pevonedistat, venetoclax, and azacitidine is safe for patients with relapsed or refractory acute myeloid leukemia (AML). Earlier studies demonstrated that this combination worked well, with most patients not experiencing severe side effects.

For the venetoclax and azacitidine pair, studies have found it generally safe, though a small number of patients reported serious side effects like pneumonia. Despite this, many patients have experienced positive results with this treatment.

In summary, both treatment combinations have been shown to be safe and effective, but it's important to weigh the potential risks and benefits. Always consult medical professionals before joining any clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Pevonedistat, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia because it targets the disease in a novel way. Unlike standard treatments that primarily focus on killing cancer cells, Pevonedistat works by inhibiting a protein called NEDD8-activating enzyme, which disrupts cancer cell survival mechanisms, potentially enhancing the effect of other drugs like Venetoclax and Azacitidine. This approach could offer a more effective way to eliminate leukemia cells and maintain remission. Additionally, combining these drugs could lead to more personalized treatment options, offering hope for patients who may not respond well to existing therapies.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that combining venetoclax and azacitidine is a well-established treatment for acute myeloid leukemia (AML) in patients unable to undergo intensive chemotherapy. Studies have found that this combination can extend patient survival compared to azacitidine alone. In this trial, one group of participants will receive the established combination of venetoclax and azacitidine. Another group will receive a combination that includes pevonedistat, which might attack cancer cells in a new way, potentially enhancing treatment effectiveness. Early results suggest that adding pevonedistat shows promise for AML patients. This trial explores whether this three-drug combination can lead to even better outcomes. ^{1 2 3 4 5}

Who Is on the Research Team?

Study Director

Principal Investigator

Takeda

Are You a Good Fit for This Trial?

Adults recently diagnosed with Acute Myeloid Leukemia (AML) who can't undergo intensive chemotherapy due to age or health issues like poor performance status, heart or lung problems, reduced kidney function, or liver disorders. Participants should not have had certain prior treatments for AML, no genetic acute promyelocytic leukemia, and must be unfit for stem cell transplantation.

Inclusion Criteria

Has clinical laboratory values within specified parameters.

I cannot receive standard chemotherapy due to my age or other health issues.

I have been diagnosed with AML according to WHO criteria.

Exclusion Criteria

My AML has affected or has a history of affecting my brain or spinal cord.

I have a history of blood cancer with a specific genetic change.

Has a WBC count ≥25 × 10^9/L

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Pevonedistat + Venetoclax + Azacitidine or Venetoclax + Azacitidine in 28-day cycles

Up to 36 months

Regular visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (optional)

Participants may continue treatment as long as they are benefiting from it

Long-term

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Pevonedistat
• Venetoclax

Trial Overview The trial is testing if adding Pevonedistat to the combination of Venetoclax and Azacitidine improves outcomes in AML patients compared to just Venetoclax and Azacitidine. Patients will receive these drugs in cycles lasting 28 days each and may continue treatment as long as it's beneficial.

How Is the Trial Designed?

Group I: Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2 Experimental Treatment 3 Interventions

Pevonedistat 20 mg/m\^2 as a 60-minute IV infusion on Days 1, 3, and 5 in each 28-day cycle plus venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m\^2 IV or SC dosing on Day 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.

Group II: Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2 Active Control 2 Interventions

Venetoclax 100 mg tablet orally on Day 1; 200 mg on Day 2; thereafter, at 400 mg on Day 3 through Day 28 in Cycle 1 (cycle length= 28 days) and 400 mg on Days 1 through 28 in Cycle 2 and beyond if tolerated. Following the confirmation of remission in Cycle 1 or thereafter, venetoclax 400 mg was administered on Day 1 through 21 or 28 as per Investigator's discretion, plus azacitidine 75 mg/m\^2 intravenous (IV) or subcutaneous (SC) dosing on Days 1 through 7 or Days 1 through 5, Days 8, and 9 in each cycle up to primary completion date: 06 September 2022.

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

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Takeda

Lead Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04266795

NCT04266795 | A Study of Pevonedistat and Venetoclax ... Pevonedistat is being tested to treat people who have AML. This study will compare the improvement in EFS in Arm A: Pevonedistat + Venetoclax + Azacitidine ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38572562/

A phase I study of pevonedistat, azacitidine, and ... To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/10428194.2024.2431878

Azacitidine and venetoclax with or without pevonedistat in ... This phase 2 study investigated pevonedistat + azacitidine + venetoclax (n = 83) versus azacitidine + venetoclax (n = 81) in patients with newly diagnosed ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11367232/

A phase I study of pevonedistat, azacitidine, and venetoclax in ... The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. ( ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03862157

NCT03862157 | Azacitidine, Venetoclax, and Pevonedistat ... Giving azacitidine, venetoclax, and pevonedistat may work better in treating patients with acute myeloid leukemia. Detailed Description. PRIMARY OBJECTIVES ...