What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML), such as the combination of venetoclax and azacitidine, are associated with several side effects. These include febrile neutropenia, neutropenia, thrombocytopenia, nausea, vomiting, constipation, diarrhea, hypokalemia, peripheral edema, and infections. The addition of pevonedistat, a NEDD8-activating enzyme inhibitor, to this regimen is being studied, but the side effects are expected to be similar, with potential additional toxicities due to the novel agent.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myeloid Leukemia (AML), particularly for patients who are not candidates for intensive chemotherapy. Venetoclax, a BCL-2 inhibitor, has been approved in combination with hypomethylating agents (HMAs) like Azacitidine or Decitabine for newly diagnosed AML in older adults or those with comorbidities. Azacitidine and Decitabine, both HMAs, have shown superior survival rates compared to supportive care. Other notable FDA-approved drugs include Ivosidenib for IDH1-mutated AML and Enasidenib for IDH2-mutated AML. These treatments aim to improve outcomes for patients with specific genetic mutations or those who are unfit for intensive therapy.

What other types of research exist?

Promising novel alternatives to Pevonedistat for AML treatment include: 1) Venetoclax, a BCL-2 inhibitor, which is effective in combination with HMAs like azacitidine or decitabine. 2) Ivosidenib, an IDH1 inhibitor, for patients with IDH1 mutations. 3) Enasidenib, an IDH2 inhibitor, for patients with IDH2 mutations. 4) Gilteritinib, an FLT3 inhibitor, particularly for patients with FLT3 mutations. These agents have shown significant efficacy in clinical trials and are considered promising options for AML treatment in 2024.

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Nucleoside metabolic inhibitor

Pevonedistat + Venetoclax + Azacitidine for Acute Myeloid Leukemia (PEVENAZA Trial)

Phase 2

Waitlist Available

Research Sponsored by Takeda

Eligibility Criteria Checklist

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

Must have

Be older than 18 years old

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 36 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug combination for adults with AML who can't handle intensive chemotherapy. The drugs work together to stop cancer cells from growing and help kill them. Venetoclax combined with azacitidine has become a new standard of care for patients unfit for intensive chemotherapy.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include reactions at the infusion site, fatigue, nausea, low blood counts leading to increased infection risk or bleeding complications. Organ-specific side effects such as heart or liver issues could also occur.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 36 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 36 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 36 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Event-Free Survival (EFS)

Secondary study objectives

Duration of CR and CRi

Overall Response Rate (ORR)

Overall Survival (OS)

+7 more

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

2Treatment groups

Experimental Treatment

Active Control

Group I: Pevonedistat 20 mg/m^2 + Venetoclax 100/200/400 mg + Azacitidine 75 mg/m^2Experimental Treatment3 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^2Active Control2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Pevonedistat

2021

Completed Phase 3

~770

Azacitidine

2012

Completed Phase 3

~1440

Venetoclax

2019

Completed Phase 3

~2200

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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 hypomethylating agents (HMAs) like azacitidine and decitabine, and targeted therapies such as venetoclax. Azacitidine and decitabine work by inhibiting DNA methylation, which can reactivate tumor suppressor genes and induce cancer cell death. Venetoclax targets the BCL-2 protein, promoting apoptosis in leukemia cells. Pevonedistat, a NEDD8-activating enzyme inhibitor, disrupts protein degradation pathways, leading to the accumulation of defective proteins and cell death. These mechanisms are crucial for AML patients as they offer targeted approaches to kill leukemia cells while potentially reducing the side effects associated with traditional chemotherapy.

Molecular targeting in acute myeloid leukemia.Childhood acute myeloid leukaemia.