What side effects are associated with this type of intervention?

Azacitidine, a common treatment for Myelodysplastic Syndrome, is associated with several side effects. These include hematologic toxicities such as neutropenia, thrombocytopenia, and anemia. Patients may also experience gastrointestinal symptoms like nausea, vomiting, diarrhea, and constipation. Other side effects can include febrile neutropenia, infections, and peripheral edema. The combination of azacitidine with other agents, such as venetoclax, can increase the incidence of these adverse effects.

What prior FDA approvals exist?

Azacitidine and Decitabine, both DNA methyltransferase inhibitors, are FDA-approved for the treatment of Myelodysplastic Syndrome (MDS). These drugs help restore normal gene function by inhibiting DNA methylation. Lenalidomide is approved for MDS with deletion 5q. Eltrombopag is being studied in combination with azacitidine for its potential benefits on hematopoietic stem and progenitor cells in MDS patients. Pevonedistat, a NEDD8-activating enzyme inhibitor, is currently under investigation in combination with Azacitidine but has not yet received FDA approval for MDS.

What other types of research exist?

Promising novel alternatives for MDS treatment in 2024 include: 1) Venetoclax in combination with hypomethylating agents (HMAs) like Azacitidine or Decitabine, which has shown improved response rates and survival in AML and MDS patients. 2) Ivosidenib for patients with IDH1 mutations, which has demonstrated efficacy in clinical trials. 3) Gilteritinib, an FLT3 inhibitor, in combination with Azacitidine, which has shown higher overall response rates in preliminary studies. These alternatives offer new hope for MDS patients and should be discussed with a healthcare provider.

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DNA Methyltransferase Inhibitor

Pevonedistat + Azacitidine for Advanced Leukemias (PANTHER Trial)

Phase 3

Waitlist Available

Research Sponsored by Millennium Pharmaceuticals, Inc.

Eligibility Criteria Checklist

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

Must have

Has MDS or CMML with one of the following Prognostic Risk Categories based on the Revised International Prognostic Scoring System (IPSS-R): Very high (>6 points), High (>4.5-6 points), Intermediate (>3-4.5 points) with >=5% bone marrow myeloblasts

Has Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2

Must not have

Participants with AML with a WBC count >50,000/mcL

Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to year 1

Awards & highlights

Pivotal Trial

No Placebo-Only Group

Summary

This trial tests whether combining pevonedistat with azacitidine improves survival in patients with high-risk blood cancers. The combination aims to stop cancer cell growth and kill the cells through different methods. Azacitidine has been shown to improve survival in patients with high-risk blood cancers, and it is often used in combination with other drugs to enhance its effectiveness.

Who is the study for?

This trial is for adults with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (AML). They should have certain risk scores based on their condition, be able to perform daily activities with minimal help, and not have had previous specific cancer treatments. People can't join if they've had another cancer in the last 2 years, severe infections, HIV/hepatitis B/C, heart problems within the past 6 months, or are on strong CYP3A inducers.

What is being tested?

The study tests whether combining pevonedistat with azacitidine improves survival without disease progression compared to just azacitidine alone in patients. An 'event' refers to death or worsening of the disease. Patients will be randomly assigned to one of these treatment groups.

What are the potential side effects?

Possible side effects include reactions at injection sites, blood cell count changes leading to increased infection risk or bleeding tendencies, gastrointestinal symptoms like nausea and vomiting, fatigue and weakness. Each patient's experience may vary.

Eligibility Criteria

Inclusion Criteria

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

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My condition is MDS or CMML and falls into a high-risk category.

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I can take care of myself and am up and about more than half of my waking hours.

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My AML is moderate and I have a high risk score for intensive chemotherapy.

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I have been diagnosed with MDS, CMML, or low-blast AML with WBC under 13,000/mcL.

Exclusion Criteria

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

Select...

My white blood cell count is over 50,000 due to AML.

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I haven't had or been treated for another cancer in the last 2 years.

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I have a known heart or lung condition.

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I have been treated for my blood disorder with chemotherapy or drugs like decitabine or azacitidine.

Select...

I have a severe infection that is not under control.

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I haven't taken strong CYP3A inducers in the last 14 days.

Select...

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

Select...

I have severe liver problems or cirrhosis.

Select...

I have acute promyelocytic leukemia.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to year 1

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to year 1

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to year 1 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 Complete Remission (CR)

Duration of Complete Remission + Complete Remission With Incomplete Blood Count Recovery (CRi)

Duration of Overall Response (OR)

+25 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

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

No Placebo-Only Group

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

Trial Design

2Treatment groups

Experimental Treatment

Group I: Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2Experimental Treatment2 Interventions

Azacitidine 75 mg/m\^2 IV or SC injection on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m\^2 IV infusion, on Days 1, 3, and 5 in 28-day treatment cycles until disease progression or unacceptable toxicity or up to approximately 42 months.

Group II: Azacitidine 75 mg/m^2Experimental Treatment1 Intervention

Azacitidine 75 milligram per square meter (mg/m\^2) intravenous (IV) or subcutaneous (SC) injection on Days 1 to 5, Days 8 and 9, in 28-day treatment cycles until disease progression or unacceptable toxicity or up to approximately 42 months.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Azacitidine

2012

Completed Phase 3

~1440

Pevonedistat

2021

Completed Phase 3

~770

0 / 13Eligibility 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

Azacitidine, a DNA methyltransferase inhibitor, works by hypomethylating DNA and reactivating tumor suppressor genes, thereby reducing the proliferation of abnormal blood cells. Pevonedistat, a NEDD8-activating enzyme inhibitor, disrupts protein degradation pathways, leading to cell cycle arrest and apoptosis in malignant cells. These mechanisms are crucial for MDS patients as they target the disease's underlying pathophysiology, potentially improving blood counts and reducing the risk of progression to acute myeloid leukemia.

The development of pevonedistat in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML): hope or hype?