Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy

NCT04090736 | Active Not Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: PEVOLAM
• Study Type: interventional
• Target: 302
• Locations: 1 country
• Sites: 62

Brief Summary

Randomized phase III, multicentre, open label clinical trial to compare pevonedistat in combination with azacytidine versus azacytidine alone, which can be considered a standard of care for patients with newly diagnosed acute myeloid leukemia not eligible for intensive chemotherapy (thus not eligible for an allogeneic hematopoietic stem cell transplant.

Conditions

Leukemia, Myeloid, Acute

Keywords

Leukemia; Myeloid; Acute; Pevonedistat; Azacitidine; Randomized; Clinical trial

Outcome Measures

Primary Outcomes (1)

• Overall survival (OS)

  Time from the date of randomization to the date of death.

  through study completion, an average of 1 year

Secondary Outcomes (25)

• Event-free survival (EFS)

  through study completion, an average of 1 year

• Composite complete remission

  through study completion, an average of 1 year

• Overall response rate

  through study completion, an average of 1 year

• Cumulative incidence of relapse

  through study completion, an average of 1 year

• Health status/quality of life

  through study completion, an average of 1 year

Study Arms (2)

Arm A: Pevonedistat plus Azacitidine

EXPERIMENTAL

Pevonedistat 20 mg/m2 IV on days 1, 3, and 5 plus Azacitidine 75 mg/m2 subcutaneous administered on a 5-on/2-off \[weekend\]/2-on schedule in 28-day cycles (intravenous Azacitidine can be administered for any patients who have non-tolerated local reactions)

Drug: Pevonedistat; Drug: Azacitidine

Arm B: Azacitidine

ACTIVE COMPARATOR

Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off \[weekend\]/2-on schedule in 28-day cycle (intravenous azacitidine can be administered for any patients who have non-tolerated local reactions)

Drug: Azacitidine

Interventions

Pevonedistat DRUG

Pevonedistat 20 mg/m2 intravenous on days 1, 3, and 5 (28-day cycles)

Arm A: Pevonedistat plus Azacitidine

Azacitidine DRUG

Azacitidine 75 mg/m2 subcutaneous on a 5-on/2-off \[weekend\]/2-on schedule (28-day cycle). Intravenous for patients who have non-tolerated local reactions

Arm A: Pevonedistat plus Azacitidine; Arm B: Azacitidine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients 18 years or older
• Morphological diagnosis of Acute Myeloid Leukemia (AML) (WHO criteria 2008)
• 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).
• Newly diagnosed AML
• 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:
• ≥ 75 years of age
• 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).
• 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):

You may not qualify if:

• 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.
• Subject has history MPN with BCR-ABL1 translocation and AML with BCR-ABL1 translocation.
• Genetic diagnosis of acute promyelocytic leukemia.
• Eligible for intensive chemotherapy and/or allogeneic stem cell transplantation.
• The reason a patient is not eligible for intensive chemotherapy must be documented in the electronic case report form (eCRF).
• Patients with either clinical evidence of or history of central nervous system involvement by AML.
• 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.
• 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.
• Subject has a white blood cell count \> 50 × 109/L.
• Contraindications for PEVO or AZA.
• Known hypersensitivity to pevonedistat or its excipients.
• 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).
• 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.
• 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).
• 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:

Sponsors & Collaborators

• PETHEMA Foundation: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Dynamic Science S.L.: collaborator

Study Sites (62)

Complejo Hospitalario Universitario de Santiago

Santiago de Compostela, A Coruña, 15706, Spain

Location

Hospital Txagorritxu

Vitoria-Gasteiz, Alava, 01009, Spain

Location

ICO Badalona- Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, 08916, Spain

Location

ICO Hospitalet- Hospital Duran i Reynals

Hospitalet Del Llobregat, Barcelona, 08908, Spain

Location

Hospital Universitario Donostia

San Sebastián, Guipuzcoa, Spain

Location

Complejo Hospitalario de Jaén

Jaén, Jaen, 23007, Spain

Location

Complejo Hospitalario Universitario de Gran Canaria Dr. Negrín

Las Palmas de Gran Canaria, Las Palmas, 35020, Spain

Location

Hospital Universitario Quirón Madrid

Pozuelo de Alarcón, Madrid, 28223, Spain

Location

Hospital Universitario Infanta Sofía

San Sebastián de los Reyes, Madrid, 28702, Spain

Location

Hospital Regional Universitario de Málaga

Málaga, Malaga, 29010, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Malaga, 29010, Spain

Location

Hospital General Universitario Santa Lucía

Cartagena, Murcia, 30200, Spain

Location

Hospital Universitario Central de Asturias

Oviedo, Principality of Asturias, 33006, Spain

Location

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Santa Cruz De Tenerife, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Sevila, 41013, Spain

Location

Hospital General Nuestra Señora del Prado

Talavera de la Reina, Toledo, 45600, Spain

Location

Hospital Universitario de Cruces

Barakaldo, Vizcaya, 48903, Spain

Location

Hospital Universitario de Basurto

Bilbao, Vizcaya, 48013, Spain

Location

Hospital Universitario de Galdakao

Galdakao, Vizcaya, 48960, Spain

Location

Complejo Hospitalario Universitario A Coruña

A Coruña, 15006, Spain

Location

Complejo Hospitalario Universitario de Albacete

Albacete, 02006, Spain

Location

Hospital General Universitario de Alicante

Alicante, 03010, Spain

Location

Complejo Hospitalario Torrecárdenas

Almería, 04004, Spain

Location

Hospital Dr. José Molina Orosa

Arrecife, Spain

Location

Hospital San Agustin

Avilés, Spain

Location

Complejo Asistencial de Ávila

Ávila, Spain

Location

Hospital Universitario de Badajoz

Badajoz, Spain

Location

Hospital del Mar

Barcelona, Spain

Location

Hospital Vithas Xanit Internacional

Benalmádena, Spain

Location

Hospital Universitario de Burgos

Burgos, 09006, Spain

Location

Hospital Universitario Puerta del Mar

Cadiz, 11009, Spain

Location

Hospital General Universitario de Castellón

Castelló, Spain

Location

Complejo Hospitalario de Cáceres

Cáceres, 10003, Spain

Location

Complejo Hospitalario Regional Reina Sofía

Córdoba, 14004, Spain

Location

Hospital General Universitario de Elche

Elche, Spain

Location

ICO Girona- Hospital Universitari Dr Josep Trueta

Girona, 17007, Spain

Location

Hospital Universitario de Guadalajara

Guadalajara, Spain

Location

Hospital Universitario Juan Ramón Jiménez

Huelva, 21005, Spain

Location

Hospital San Jorge

Huesca, Spain

Location

Complejo Hospitalario Lucus Augusti

Lugo, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, 28034, Spain

Location

Hospital Clínico San Carlos

Madrid, 28040, Spain

Location

Hospital Universitario Fundación Jiménez Díaz

Madrid, 28040, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Hospital Universitario Madrid Norte Sanchinarro

Madrid, 28050, Spain

Location

Hospital Quirón de Málaga

Málaga, Spain

Location

Hospital General Universitario Morales Meseguer

Murcia, 30008, Spain

Location

Complexo Hospitalario Universitario de Ourense

Ourense, 32005, Spain

Location

Hospital Son Llàtzer

Palma de Mallorca, Spain

Location

Complexo Hospitalario de Pontevedra

Pontevedra, 36071, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Complejo Hospitalario Universitario Nuestra Señora de la Candelaria

Santa Cruz de Tenerife, 38010, Spain

Location

Hospital General de Segovia

Segovia, Spain

Location

Hospital de Valme

Seville, Spain

Location

Hospital Universitari Joan XXIII

Tarragona, 43005, Spain

Location

Hospital Virgen de la Salud

Toledo, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, 46010, Spain

Location

Hospital Universitario Dr. Peset Aleixandre

Valencia, 46017, Spain

Location

Hospital Universitari i Politecnic La Fe

Valencia, 46026, Spain

Location

Hospital Clínico Universitario de Valladolid

Valladolid, 47003, Spain

Location

Hospital Clínico Universitario Lozano Blesa

Zaragoza, 50009, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, 50009, Spain

Location

Related Publications (10)

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• Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.

  PMID: 14673054 BACKGROUND

• Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6. doi: 10.1038/nature07884.

  PMID: 19360080 BACKGROUND

• Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res. 2010 Dec 15;70(24):10310-20. doi: 10.1158/0008-5472.CAN-10-2062.

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• Milhollen MA, Narayanan U, Soucy TA, Veiby PO, Smith PG, Amidon B. Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer Res. 2011 Apr 15;71(8):3042-51. doi: 10.1158/0008-5472.CAN-10-2122. Epub 2011 Apr 12.

  PMID: 21487042 BACKGROUND

• Sarantopoulos J, Shapiro GI, Cohen RB, Clark JW, Kauh JS, Weiss GJ, Cleary JM, Mahalingam D, Pickard MD, Faessel HM, Berger AJ, Burke K, Mulligan G, Dezube BJ, Harvey RD. Phase I Study of the Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (TAK-924/MLN4924) in Patients with Advanced Solid Tumors. Clin Cancer Res. 2016 Feb 15;22(4):847-57. doi: 10.1158/1078-0432.CCR-15-1338. Epub 2015 Sep 30.

  PMID: 26423795 RESULT

• Swords RT, Coutre S, Maris MB, Zeidner JF, Foran JM, Cruz J, Erba HP, Berdeja JG, Tam W, Vardhanabhuti S, Pawlikowska-Dobler I, Faessel HM, Dash AB, Sedarati F, Dezube BJ, Faller DV, Savona MR. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018 Mar 29;131(13):1415-1424. doi: 10.1182/blood-2017-09-805895. Epub 2018 Jan 18.

  PMID: 29348128 RESULT

• Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher C, Sandhu I, Bernal del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Dohner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. doi: 10.1182/blood-2015-01-621664. Epub 2015 May 18.

  PMID: 25987659 RESULT

• Shah JJ, Jakubowiak AJ, O'Connor OA, Orlowski RZ, Harvey RD, Smith MR, Lebovic D, Diefenbach C, Kelly K, Hua Z, Berger AJ, Mulligan G, Faessel HM, Tirrell S, Dezube BJ, Lonial S. Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma. Clin Cancer Res. 2016 Jan 1;22(1):34-43. doi: 10.1158/1078-0432.CCR-15-1237. Epub 2015 Nov 11.

  PMID: 26561559 RESULT

• Bhatia S, Pavlick AC, Boasberg P, Thompson JA, Mulligan G, Pickard MD, Faessel H, Dezube BJ, Hamid O. A phase I study of the investigational NEDD8-activating enzyme inhibitor pevonedistat (TAK-924/MLN4924) in patients with metastatic melanoma. Invest New Drugs. 2016 Aug;34(4):439-49. doi: 10.1007/s10637-016-0348-5. Epub 2016 Apr 8.

  PMID: 27056178 RESULT

Related Links

• Web page of the sponsor of the study

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia

Interventions

pevonedistat; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, prospective, multicenter, open label study.

Study Record Dates

• First Submitted: September 11, 2019
• First Posted: September 16, 2019
• Study Start: September 24, 2019
• Primary Completion: June 30, 2023
• Study Completion: June 30, 2025
• Last Updated: March 17, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (62)