NCT03268954: PANTHER

Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)

Completed Phase 3 Results posted Last updated 29 October 2025

What this trial tests

Phase 3 trial testing Azacitidine in Myelodysplastic Syndrome in 454 participants. Completed in 14 October 2024.

Timeline

28 November 2017

Primary endpoint
28 May 2021

14 October 2024

Quick facts

Lead sponsor	Takeda
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	454
Start date	28 November 2017
Primary completion	28 May 2021
Estimated completion	14 October 2024
Sites	242 locations across Italy, Japan, Poland, South Korea, Russia, Belgium, Mexico, United States

Drugs / interventions tested

• Azacitidine (azacitidine) — full drug profile →
• Pevonedistat — full drug profile →

Conditions studied

• Myelodysplastic Syndrome — all drugs for Myelodysplastic Syndrome →
• Leukemia, Myelomonocytic, Chronic — all drugs for Leukemia, Myelomonocytic, Chronic →
• Leukemia, Myeloid, Acute — all drugs for Leukemia, Myeloid, Acute →

Sponsor

Takeda — full company profile →

Who can join

18 and older, any sex, with Myelodysplastic Syndrome or Leukemia, Myelomonocytic, Chronic. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Event-Free Survival (EFS) Primary · From randomization until transformation to acute myeloid leukemia, or death due to any cause: up to approximately 42 months

EFS was defined as the time from randomization to the date of an EFS event. An EFS event was defined as death or transformation to acute myelogenous leukemia (AML) (World Health Organization \[WHO\] classification as a participant having greater than 20 % blasts in the blood or marrow and an increase of blast count by 50%), whichever event occurred first, in participants with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemias (CMML). An EFS event was defined as death in participants with low-blast AML.

Group	Value	95% CI
Azacitidine 75 mg/m^2	15.7	14.42 – 19.68
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	17.7	13.63 – 20.24

Overall Survival (OS) Secondary · Up to approximately 6.9 years

Overall survival was defined as the time from randomization to death from any cause.

Group	Value	95% CI
Azacitidine 75 mg/m^2	16.8	14.92 – 20.11
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	20.3	17.97 – 22.60

Kaplan-Meier Estimates of Six-Month Survival Rate Secondary · Month 6

Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of Month 6 from randomization are presented.

Group	Value	95% CI
Azacitidine 75 mg/m^2	0.825	0.767 – 0.869
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	0.810	0.752 – 0.856

Kaplan-Meier Estimates of One-Year Survival Rate Secondary · Year 1

Kaplan-Meier estimates for the probability (expressed as a percentage) of participants that survived at the end of the first year from randomization are presented.

Group	Value	95% CI
Azacitidine 75 mg/m^2	0.693	0.626 – 0.751
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	0.646	0.578 – 0.706

Thirty-Day Mortality Reported as Number of Participants Who Died Up to Day 30 Secondary · Up to Day 30

30-day mortality was defined as number of participants who died within 30 days from the first dose of study drug.

Group	Value	95% CI
Azacitidine 75 mg/m^2	6
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	5

Sixty-Day Mortality Reported as Number of Participants Who Died Up to Day 60 Secondary · Up to Day 60

60-day mortality was defined as number of participants who died within 60 days from the first dose of study drug.

Group	Value	95% CI
Azacitidine 75 mg/m^2	15
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	14

Time to Acute Myelogenous Leukemia (AML) Transformation in Higher-Risk Myelodysplastic Syndromes (HR MDS), Higher-Risk Chronic Myelomonocytic Leukemias (HR CMML) and HR MDS/CMML Participants Secondary · From randomization until transformation to AML (up to approximately 42 months)

Time to AML transformation in HR MDS and CMML participants was defined as time from randomization to documented AML transformation as determined by the independent review committee (IRC) assessment. Participants who died before progression to AML were censored. Transformation to AML was defined, according to WHO classification, as a participant having 20% blasts in the blood or marrow and increase of blast count by 50%.

HR MDS Participants

Group	Value	95% CI
Azacitidine 75 mg/m^2	35.6	26.51 – NA
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	23.29 – NA

HR CMML Participants

Group	Value	95% CI
Azacitidine 75 mg/m^2	NA	NA – NA
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	NA – NA

HR MDS/CMML Participants

Group	Value	95% CI
Azacitidine 75 mg/m^2	35.6	29.04 – NA
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	NA	24.28 – NA

Number of Participants With Complete Remission (CR) and CR+ Complete Remission With Incomplete Blood Count Recovery (CRi) Secondary · From randomization until CR (up to approximately 42 months)

CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to \>=11 gram per deciliter (g/dL) hemoglobin (Hgb),\>=100\*10\^9/liter (/L) platelets (pl),\>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. CR for low-blast AML: morphologic leukemia-free state, neutrophils of more than 1.0\*10\^9/L and pl of \>=100\*10\^9/L, transfusion independence, and no residual evidence of extramedullary leukemia. CR with incomplete blood count recovery (CRi) for low-blast AML: participants fulfill all of the criteria

Group	Value	95% CI
Azacitidine 75 mg/m^2	71
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	63

Number of Participants With CR and Marrow CR Secondary · From randomization until CR or marrow CR (up to approximately 42 months)

Disease responses for HR MDS or CMML are based on the International Working Group (IWG) Response Criteria for MDS. CR for HR MDS or CMML is defined as \<=5% myeloblasts with normal maturation of all cell lines in the bone marrow, and \>=11 g/dL Hgb, \>=100\*10\^9/L platelets (pl), \>=1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment.

Group	Value	95% CI
Azacitidine 75 mg/m^2	91
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	87

Number of Participants With CR, Partial Remission (PR) and Hematologic Improvement (HI) Secondary · From randomization until, CR, PR or HI (up to approximately 42 months)

Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%. HI: Hgb increase \>=1.5 g/dL if \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100

Group	Value	95% CI
Azacitidine 75 mg/m^2	77
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	76

Number of Participants With CR and Marrow CR and PR Secondary · From randomization until CR or Marrow CR and PR (up to approximately 42 months)

Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still \>5%.

Group	Value	95% CI
Azacitidine 75 mg/m^2	91
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	87

Number of Participants With CR and Marrow CR, PR and Hematologic Improvement (HI) Secondary · From randomization until CR, marrow CR, PR or HI (up to approximately 42 months)

Disease responses for HR MDS/CMML based on Modified IWG Response Criteria for MDS. CR: \<=5% myeloblasts with normal maturation of all bone marrow cell lines, \>=11 g/dL Hgb, \>=100\*10\^9/L pl, \>=1.0\*10\^9/L neutrophils,0% blasts in peripheral blood. Marrow CR: Bone marrow: \<=5% myeloblasts and decrease by \>=50% over pretreatment. PR: all CR criteria met except bone marrow blasts \>=50% decrease over pretreatment but still\>5%. HI: Hgb increase \>=1.5 g/dL if baseline \<11 g/dL; pl increase \>=30\*10\^9/L if baseline\>20\*10\^9/L or increases from \<20\*10\^9/L to \>20\*10\^9/L and by at

Group	Value	95% CI
Azacitidine 75 mg/m^2	112
Pevonedistat 20 mg/m^2 + Azacitidine 75 mg/m^2	117

Adverse events — posted to ClinicalTrials.gov

Time frame: From first dose of study drug up to end of study (up to approximately 6.9 years). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Azacitidine 75 mg/m^2

Serious: 145/220 (66%)

Deaths: 153/220

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

Serious: 156/223 (70%)

Deaths: 150/223

Serious adverse events (243 terms)

Reaction	System	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + A…
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Pneumonia	Infections and infestations	—	—
Pyrexia	General disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Septic shock	Infections and infestations	—	—
Sepsis	Infections and infestations	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Cellulitis	Infections and infestations	—	—
Urinary tract infection	Infections and infestations	—	—
Cardio-respiratory arrest	Cardiac disorders	—	—
Lower respiratory tract infection	Infections and infestations	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
COVID-19 pneumonia	Infections and infestations	—	—
Infection	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Respiratory tract infection	Infections and infestations	—	—
Acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
COVID-19	Infections and infestations	—	—
Cardiac failure	Cardiac disorders	—	—
Cerebrovascular accident	Nervous system disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
General physical health deterioration	General disorders	—	—
Haemorrhage intracranial	Nervous system disorders	—	—
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	—	—

Other adverse events (51 terms — click to expand)

Reaction	System	Azacitidine 75 mg/m^2	Pevonedistat 20 mg/m^2 + A…
Constipation	Gastrointestinal disorders	—	—
Anaemia	Blood and lymphatic system disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Neutropenia	Blood and lymphatic system disorders	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—
Diarrhoea	Gastrointestinal disorders	—	—
Pyrexia	General disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Asthenia	General disorders	—	—
Fatigue	General disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Neutrophil count decreased	Investigations	—	—
Platelet count decreased	Investigations	—	—
Oedema peripheral	General disorders	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Headache	Nervous system disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Dizziness	Nervous system disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Blood creatinine increased	Investigations	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—
Insomnia	Psychiatric disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Urinary tract infection	Infections and infestations	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Contusion	Injury, poisoning and procedural complications	—	—
Hypertension	Vascular disorders	—	—
Injection site erythema	General disorders	—	—
Alanine aminotransferase increased	Investigations	—	—
Pneumonia	Infections and infestations	—	—
Haemorrhoids	Gastrointestinal disorders	—	—
Aspartate aminotransferase increased	Investigations	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—
Stomatitis	Gastrointestinal disorders	—	—
White blood cell count decreased	Investigations	—	—

Most-reported serious reactions: Febrile neutropenia, Pneumonia, Pyrexia, Anaemia, Septic shock, Sepsis, Thrombocytopenia, Cellulitis.

Data from ClinicalTrials.gov NCT03268954 adverse events section.

Sponsor's own description

The purpose of this study is to determine whether the combination of pevonedistat and azacitidine improves event-free survival (EFS) when compared with single-agent azacitidine. (An event is defined as death or transformation to AML in participants with MDS or CMML, whichever occurs first, and is defined as death in participants with low-blast AML).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
   Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
2. Small Molecule NF-κB Pathway Inhibitors in Clinic.
   Ramadass V, Vaiyapuri T, Tergaonkar V. · · 2020 · cited 154× · PMID 32708302 · DOI 10.3390/ijms21145164
3. Recent advances in targeted therapies in acute myeloid leukemia.
   Bhansali RS, Pratz KW, Lai C. · · 2023 · cited 151× · PMID 36966300 · DOI 10.1186/s13045-023-01424-6
4. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends.
   Nepali K, Liou JP. · · 2021 · cited 122× · PMID 33840388 · DOI 10.1186/s12929-021-00721-x
5. Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML.
   Adès L, Girshova L, Doronin VA, Díez-Campelo M, et al · · 2022 · cited 96× · PMID 35728048 · DOI 10.1182/bloodadvances.2022007334
6. Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms.
   Fisher DAC, Fowles JS, Zhou A, Oh ST. · · 2021 · cited 85× · PMID 34140953 · DOI 10.3389/fimmu.2021.683401
7. Current challenges and unmet medical needs in myelodysplastic syndromes.
   Platzbecker U, Kubasch AS, Homer-Bouthiette C, Prebet T. · · 2021 · cited 67× · PMID 34045662 · DOI 10.1038/s41375-021-01265-7
8. Phase Ib study of pevonedistat, a NEDD8-activating enzyme inhibitor, in combination with docetaxel, carboplatin and paclitaxel, or gemcitabine, in patients with advanced solid tumors.
   Lockhart AC, Bauer TM, Aggarwal C, Lee CB, et al · · 2019 · cited 65× · PMID 29781056 · DOI 10.1007/s10637-018-0610-0