New combo aims to boost survival in older AML patients

NCT ID NCT04090736

Disease control Sponsor: PETHEMA Foundation Source: ClinicalTrials.gov ↗

First seen Jun 27, 2026 · Last updated Jun 27, 2026

Summary

This phase 3 trial compares a two-drug combination (pevonedistat plus azacitidine) against azacitidine alone in 302 older or unfit adults newly diagnosed with acute myeloid leukemia (AML) who cannot have standard intensive chemotherapy. The main goal is to see if the combination improves overall survival. Participants receive treatment in 28-day cycles, and the study is no longer recruiting new patients.

What this could mean

Our plain-language read of the trial. This is informational only, not medical advice or a prediction.

Active substance: Pevonedistat combined with azacitidine
What this could lead to: If successful, this combination could offer a new treatment option that improves survival for older or frail patients with acute myeloid leukemia who cannot tolerate standard chemotherapy.
What could go wrong: This is a phase 3 trial, but results are not yet reported. The combination may not improve survival over azacitidine alone and could cause additional side effects. It is not a cure, and patients still need ongoing treatment.

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Study facts

What this study's own registry entry says, in plain language.

Phase

Phase 3

Large-scale testing in a bigger group. Usually the last step before a treatment can be approved.

Participants

302 people

The number who actually took part.

Started

Sep 2019

Expected to finish

Jul 2026

An estimate. End dates often move.

Lead sponsor

Other sponsor

The registry's catch-all category, for sponsors it does not file as a company, a government agency, or a research network.

Who can take part

This study's own entry requirements. Only the study team can say for certain whether you qualify.

Ages

18 years and older

Sex

Anyone

Healthy volunteers

Not accepted

This study is not open to healthy volunteers. The entry requirements below say who it is open to.

Show the full entry requirements

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

Inclusion Criteria: 1. Male or female patients 18 years or older 2. Morphological diagnosis of Acute Myeloid Leukemia (AML) (WHO criteria 2008) 3. Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance status (PS) of 0 to 3 (ECOG 0-2 for patients greater than or equal to 75 years old). 4. Newly diagnosed AML 5. Patient must be considered be ineligible for treatment with a standard Ara-C and anthracycline induction regimen due to age or co-morbidities defined by one of the following: 1. ≥ 75 years of age 2. Or ≥ 18 to 74 years of age with at least one of the following: * ECOG Performance Status of 2 or 3; * Cardiac history of cardiac heart failure requiring treatment or Ejection Fraction ≤ 50% or chronic stable angina; * Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) ≤ 65% or Forced Expiratory Volume in 1 second (FEV1) ≤ 65% or significant history of chronic pulmonary obstructive disease; * Glomerular filtration rate (GFR) ≥ 30 mL/min to \< 50 ml/min or levels of creatinine between the upper limit of the normal range (ULN) and 2.5 mg/dL (≤ 250 μmol/l). * Hepatic impairment with total bilirubin \> 1.5 to ≤ 3 × ULN or with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 2.5×ULN to ≤ 5×ULN * Non active/controlled prior neoplastic disease * Any other patient´s comorbidity or disease condition that the physician judges to be incompatible with intensive chemotherapy must be reviewed, documented, and approved by the Sponsor before study enrollment). 6. Clinical laboratory values within the following parameters (repeat within 3 days before the first dose of study drug if laboratory values used for randomization were obtained more than 3 days before the first dose of study drug): * Total bilirubin ≤ 1.5 × ULN except in patients with Gilbert's syndrome or ≤ 3 × ULN if elevation is attributed to underlying leukemia. Patients with Gilbert's syndrome may enroll with direct bilirubin ≤3 × ULN of the direct bilirubin. Elevated indirect bilirubin due to posttransfusion hemolysis is allowed. * ALT and AST ≤ 2.5×ULN or ≤ 5×ULN if elevation is attributed to underlying leukemia. * Adequate renal function as demonstrated by a creatinine clearance ≥ 30 mL/min (calculated by the Cockcroft Gault formula, (see Appendix 5). * Albumin \>2.7 g/dL. 7. Subject has a white blood cell count \<50 × 109/L. Patients who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria before starting therapy. 8. Female subjects must be either postmenopausal for at least 1 year before screening (see Appendix 12 for definition) OR permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) OR Women of Childbearing Potential (WOCBP) must agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception (see Appendix 11), at the same time, from the time of signing the informed consent through 4 months after the last dose of study drug (female and male condoms should not be used together), or Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female subjects of childbearing potential must have negative results for pregnancy test performed and must not be lactating and breastfeeding. 9. Male subjects even if surgically sterilized (i.e., status post vasectomy), who are sexually active, must agree, from Study Day 1 through at least 4 months after the last dose of study drug, to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug (female and male condoms should not be used together), or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner\] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.) 10. Subject must voluntarily sign and date an informed consent, approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care. Exclusion Criteria: 1. Previous treatment for myelodysplastic síndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) or myeloproliferative neoplasms (MPN), with chemotherapy or other antineoplastic agents including HMAs (up to 2 cycles of Hypomethylating agents (HMA) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug. 2. Subject has history MPN with BCR-ABL1 translocation and AML with BCR-ABL1 translocation. 3. Genetic diagnosis of acute promyelocytic leukemia. 4. Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. * The reason a patient is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation is described in the inclusion criteria section * The reason a patient is not eligible for intensive chemotherapy must be documented in the electronic case report form (eCRF). 5. Patients with either clinical evidence of or history of central nervous system involvement by AML. 6. Diagnosed or treated for another malignancy within 1 year before randomization or previously diagnosed with another malignancy and have any evidence of residual disease which may compromise the administration of AZA or AZA+PEVO. 7. Psychological,social, or geographic factors that otherwise preclude the patient from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up. 8. Subject has a white blood cell count \> 50 × 109/L. 9. Contraindications for PEVO or AZA. 10. Known hypersensitivity to pevonedistat or its excipients. 11. Female patients who intend to donate eggs (ova) during the course of this study or for 4 months after receiving their last dose of study drug(s). 12. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. 13. Male patients who intend to donate sperm or father a child during the course of this study or for 4 months after receiving their last dose of study drug(s). 14. Subject is known to be positive for HIV (HIV testing is not required for eligibility assessment). Known HIV positive patients who meet the following criteria will be considered eligible: * Cluster of differentiation 4 (CD4) count \> 350 cells/mm3 * Undetectable viral load * Maintained on modern therapeutic regimens utilizing non-cytochrome P450 (CYP)-interactive agents * No history of AIDS-defining opportunistic infections 15. Subject is known to be positive for hepatitis B or C infection, with the exception of those with an undetectable viral load within 3 months (Hepatitis B or C testing is not required for eligibility assessment). 16. Known hepatic cirrhosis or severe preexisting hepatic impairment. 17. Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see Appendix 7), and/or ST elevation myocardial infarction within 6 months before first dose, or severe symptomatic pulmonary hypertension requiring pharmacologic therapy, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. As an example, well-controlled atrial fibrillation would not be an exclusion whereas uncontrolled atrial fibrillation would be an exclusion. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled. 18. Subject has chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition that in the opinion of the investigator would adversely affect his/her participating in this study. 19. Treatment with strong Cytochrome P450, family 3, subfamily A (CYP3A) inducers (see Appendix 8) within 14 days before the first dose of pevonedistat. 20. Patients with uncontrolled coagulopathy or bleeding disorder. 21. High blood pressure which cannot be controlled by standard treatments 22. Prolonged rate corrected QT (QTc) interval ≥ 500 msec, calculated according to institutional guidelines. 23. As infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control and no signs of systemic inflammatory response beyond low grade fever that makes patient clinically unstable in the opinion of the investigator. Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control. 24. Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent and until toxicity from this has resolved to grade 1 or less; if the half-life of the agent is unknown, patients must wait 4 weeks prior to first dose of study treatment. 25. Systemic antineoplastic therapy for malignant conditions other than myeloid neoplasms within 14 days before the first dose of any study drug.

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Conditions

The condition(s) this trial relates to.

acute myeloid leukemia leukemia

As listed by the trial registrant

The condition terms exactly as the trial's registrant entered them.

Leukemia, myeloid, acute

Contacts and locations

Locations

Complejo Asistencial de Ávila

Ávila, Spain
Complejo Hospitalario Lucus Augusti

Lugo, Spain
Complejo Hospitalario Regional Reina Sofía

Córdoba, 14004, Spain
Complejo Hospitalario Torrecárdenas

Almería, 04004, Spain
Complejo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain
Complejo Hospitalario Universitario Nuestra Señora de la Candelaria

Santa Cruz de Tenerife, 38010, Spain
Complejo Hospitalario Universitario de Albacete

Albacete, 02006, Spain
Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín

Las Palmas de Gran Canaria, Las Palmas, 35020, Spain
Complejo Hospitalario Universitario de Santiago

Santiago de Compostela, A Coruña, 15706, Spain
Complejo Hospitalario de Cáceres

Cáceres, 10003, Spain
Complejo Hospitalario de Jaén

Jaén, Jaen, 23007, Spain
Complexo Hospitalario Universitario de Ourense

Ourense, 32005, Spain
Complexo Hospitalario de Pontevedra

Pontevedra, 36071, Spain
Hospital Clínico San Carlos

Madrid, 28040, Spain
Hospital Clínico Universitario Lozano Blesa

Zaragoza, 50009, Spain
Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain
Hospital Clínico Universitario de Valladolid

Valladolid, 47003, Spain
Hospital Dr. José Molina Orosa

Arrecife, Spain
Hospital General Nuestra Señora del Prado

Talavera de la Reina, Toledo, 45600, Spain
Hospital General Universitario Morales Meseguer

Murcia, 30008, Spain
Hospital General Universitario Santa Lucía

Cartagena, Murcia, 30200, Spain
Hospital General Universitario de Alicante

Alicante, 03010, Spain
Hospital General Universitario de Castellón

Castelló, Spain
Hospital General Universitario de Elche

Elche, Spain
Hospital General de Segovia

Segovia, Spain
Hospital Quirón de Málaga

Málaga, Spain
Hospital Regional Universitario de Málaga

Málaga, Malaga, 29010, Spain
Hospital San Agustin

Avilés, Spain
Hospital San Jorge

Huesca, Spain
Hospital Son Llàtzer

Palma de Mallorca, Spain
Hospital Txagorritxu

Vitoria-Gasteiz, Alava, 01009, Spain
Hospital Universitari Joan XXIII

Tarragona, 43005, Spain
Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain
Hospital Universitario 12 de Octubre

Madrid, 28041, Spain
Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, 33006, Spain
Hospital Universitario Donostia

San Sebastián, Guipuzcoa, Spain
Hospital Universitario Dr. Peset Aleixandre

Valencia, 46017, Spain
Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain
Hospital Universitario Infanta Sofía

San Sebastián de los Reyes, Madrid, 28702, Spain
Hospital Universitario Juan Ramón Jiménez

Huelva, 21005, Spain
Hospital Universitario Madrid Norte Sanchinarro

Madrid, 28050, Spain
Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain
Hospital Universitario Puerta del Mar

Cadiz, 11009, Spain
Hospital Universitario Quirón Madrid

Pozuelo de Alarcón, Madrid, 28223, Spain
Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain
Hospital Universitario Virgen de la Victoria

Málaga, Malaga, 29010, Spain
Hospital Universitario Virgen del Rocío

Seville, Sevila, 41013, Spain
Hospital Universitario de Badajoz

Badajoz, Spain
Hospital Universitario de Basurto

Bilbao, Vizcaya, 48013, Spain
Hospital Universitario de Burgos

Burgos, 09006, Spain
Hospital Universitario de Canarias

San Cristóbal de La Laguna, Santa Cruz De Tenerife, Spain
Hospital Universitario de Cruces

Barakaldo, Vizcaya, 48903, Spain
Hospital Universitario de Galdakao

Galdakao, Vizcaya, 48960, Spain
Hospital Universitario de Guadalajara

Guadalajara, Spain
Hospital Universitario de Salamanca

Salamanca, 37007, Spain
Hospital Virgen de la Salud

Toledo, Spain
Hospital Vithas Xanit Internacional

Benalmádena, Spain
Hospital de Valme

Seville, Spain
Hospital del Mar

Barcelona, Spain
ICO Badalona- Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain
ICO Girona- Hospital Universitari Dr Josep Trueta

Girona, 17007, Spain
ICO Hospitalet- Hospital Duran i Reynals

Hospitalet Del Llobregat, Barcelona, 08908, Spain

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