An Efficacy and Safety Study of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Adults With Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly Patients With Acute Myeloid Leukemia (AML)

NCT02775903 | Completed Phase 2 Results DMC

• 1 other identifier: MEDI4736-MDS-001
• Study Type: interventional
• Target: 213
• Locations: 12 countries
• Sites: 103

Brief Summary

The primary objective of this study is to evaluate the efficacy of subcutaneous azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in adults with previously untreated, higher risk MDS who are not eligible for HSCT or in adults ≥ 65 years old with previously untreated AML who are not eligible for HSCT, with intermediate or poor cytogenetic risk.

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Keywords

MEDI4736; Durvalumab; Myelodysplastic Syndromes; Acute Myeloid Leukemia; Hematopoietic Stem Cell Transplantation; Azacitidine; Safety; Efficacy; PD-L1

Outcome Measures

Primary Outcomes (2)

• MDS Cohort: Overall Response Rate

  Overall response rate (ORR) is defined as the percentage of participants achieving a complete remission (CR), partial remission (PR), marrow complete remission (mCR), and/or hematological improvement (HI) based on International Working Group (IWG) 2006 response criteria for MDS and central review. CR: ≤ 5% myeloblasts in bone marrow (BM), and peripheral blood: hemoglobin ≥ 11 g/dL; platelets ≥ 100 × 10⁹/L; neutrophils ≥ 1.0 × 10⁹/L; blasts 0% PR: BM blasts decreased by ≥ 50% but still \> 5%; peripheral blood as for CR mCR: BM ≤ 5% myeloblasts and decrease by ≥ 50% HI: Any of the following: •Hemoglobin increase by ≥ 1.5 g/dL or reduction of units of red blood cell (RBC) transfusions of at least 4 RBC transfusions/8 weeks compared with pretreatment •Absolute increase in platelets of ≥ 30 × 10⁹/L if pretreatment value \> 20 × 10⁹/L or increase from \< 20 × 10⁹/L to \> 20 × 10⁹/L and by at least 100% •At least 100% increase in neutrophils and an absolute increase of \> 0.5 × 10⁹/L

  Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 239 days (AZA) and 215 days (DUR) in the AZA + DUR group and 210 days in the AZA alone group.

• AML Cohort: Overall Response Rate

  Overall response rate for AML is defined as the percentage of participants achieving an overall response of morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) based on modified IWG 2003 response criteria for AML and central review. CR: The following conditions must be met: •Absolute neutrophil count (ANC) ≥ 1.0 x10⁹/L •Platelet count ≥ 100 x10⁹/L •The bone marrow should contain less than 5% blast cells; •Auer rods should not be detectable; •No platelet, or whole blood transfusions for 7days prior to the date of the hematology assessment. CRi: Defined as a morphologic complete remission but the ANC count may be \< 1.0 x10⁹/L and/or the platelet count may be \< 100 x10⁹/L.

  Response was assessed following every 3 treatment cycles until treatment discontinuation; median duration of treatment was 198 days (AZA) and 171 days (DUR) in the AZA + DUR group and 203 days in the AZA alone group.

Secondary Outcomes (22)

• MDS Cohort: Kaplan Meier Estimate of Time to First Response

  From randomization to the earliest date any response (up to approximately 34 months)

• MDS Cohort: Kaplan Meier Estimate of Relapse-free Survival

  From randomization to to the date of disease relapse or death from any cause, whichever occurred first (up to approximately 34 months)

• MDS Cohort: Percentage of Participants Who Achieved a Cytogenetic Response

  From randomization up to approximately 34 months

• MDS Cohort: Kaplan-Meier Estimate of Progression-free Survival (PFS)

  From randomization to the first documented progressive disease (PD), relapse, or death due to any cause (up to approximately 34 months)

• MDS Cohort: Kaplan-Meier Estimate of Duration of Response

  From randomization to the first overall response, or death (up to approximately 34 months)

Study Arms (2)

Azacitidine + Durvalumab

EXPERIMENTAL

Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks (Q4W) in combination with 1500 mg intravenous durvalumab on Day 1 of every 4 week cycle for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.

Drug: Azacitidine; Biological: Durvalumab

Azacitidine Alone

ACTIVE COMPARATOR

Participants received 75 mg/m² subcutaneous azacitidine for 7 days every 4 weeks for at least 6 cycles. Participants who benefited from treatment may have continued treatment until loss of that benefit, disease progression or other treatment discontinuation criterion were met.

Drug: Azacitidine

Interventions

Azacitidine DRUG

Administered by subcutaneous injection on Days 1 to 7 of each 4-week treatment cycle.

Azacitidine + Durvalumab; Azacitidine Alone

Durvalumab BIOLOGICAL

Administered by intravenous infusion on Day 1 of every 4-week treatment cycle.

Also known as: MEDI4736

Azacitidine + Durvalumab

Eligibility Criteria

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

You may qualify if:

• For both cohorts:
• Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Female subjects of childbearing potential may participate, providing they meet the following conditions:
• Have 2 negative pregnancy tests as verified by the Investigator prior to starting any investigational product (IP) therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (Investigator's discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practices complete abstinence from heterosexual contact.
• Agree to practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to the use of a highly effective method of contraception use from 28 days prior to starting durvalumab or azacitidine, and must agree to continue using such precautions while taking durvalumab or azacitidine (including dose interruptions) and up to 90 days after the last dose of durvalumab or azacitidine. Cessation of contraception after this point should be discussed with a responsible physician.
• Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP.
• Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.
• Male subject must:
• Either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to avoid fathering a child, to use highly effective methods of contraception, male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions through 90 days after receipt of the last dose of durvalumab or azacitidine.
• Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.
• Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted.
• Willing and able to adhere to the study visit schedule and other protocol requirements.
• MDS Cohort:
• Age ≥ 18 years at the time of signing the informed consent form.

You may not qualify if:

• For both cohorts:
• Prior hematopoietic stem cell transplant.
• Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous) at the time of signing the ICF.
• Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
• Inaspirable bone marrow.
• Use of any of the following within 28 days prior to the first dose of IP:
• Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, Interleukin-11)
• Any hematopoietic growth factors (erythropoietin-stimulating agents \[ESAs\], granulocyte colony-stimulating factor (G-CSF) and other red blood cell (RBC) hematopoietic growth factors (eg, Interleukin-3)
• Any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
• Prior history of malignancies (except MDS for AML subjects), unless the subject has been free of the disease for ≥ 2 years. However, subjects with the following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[tumor, node, metastases (TNM)\] clinical staging system).
• Pregnant or breast-feeding females or females who intend to become pregnant during study participation.

Sponsors & Collaborators

• Celgene: lead

Study Sites (103)

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37203, United States

Location

University of Texas- MD Anderson

Houston, Texas, 77230, United States

Location

Medizinische Universitat Graz

Graz, 8036, Austria

Location

Medizinische Universitat Innsbruck

Innsbruck, 6020, Austria

Location

Elisabethinen Hospital Linz

Linz, 4020, Austria

Location

Salzburger Landkliniken St. Johanns-Spital

Salzburg, 5020, Austria

Location

Hanusch Krankenhaus der Stadt Wien

Vienna, 1140, Austria

Location

Local Institution - 653

Vienna, 1140, Austria

Location

AKH Wien

Wein, 1090, Austria

Location

Cliniques Universitaires St-Luc

Brussels, 1200, Belgium

Location

Grand Hopital de Charleroi

Charleroi, 6000, Belgium

Location

Local Institution - 202

Ghent, 9000, Belgium

Location

UH Gent

Ghent, 9000, Belgium

Location

UH Gasthuisberg

Leuven, 3000, Belgium

Location

Cliniques Universitaires UCL de Mont-Godine

Yvoir, 5530, Belgium

Location

University of Alberta

Edmonton, Alberta, T6g2b7, Canada

Location

CancerCare Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

Location

Saint John Regional Hospital

Saint John, New Brunswick, E2L 4L2, Canada

Location

Ottawa General Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Princess Margaret Cancer Centre

Toronto, Ontario, M5G 2M9, Canada

Location

CHUM - Notre Dame

Montreal, Quebec, H2L 4M1, Canada

Location

Centre Hospitalier Universitaire d' Angers

Angers, 67091, France

Location

Hopital Avicenne

Bobigny, 93009, France

Location

Hopital Henri Mondor

Créteil, 94010, France

Location

Centre Hospitalier Universitaire de Grenoble Hopital Albert Michallon

La Tronche, 38700, France

Location

Centre Leon Berard

Lyon, 69008, France

Location

Local Institution - 261

Lyon, 69008, France

Location

CHRU de Nantes - Hotel Dieu

Nantes, 44093, France

Location

Hopital Saint Louis

Paris, 75010, France

Location

Local Institution - 251

Paris, 75010, France

Location

CHU Bordeaux

Pessac, 33604, France

Location

Local Institution - 254

Pessac, 33604, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

IUCT Oncopole

Toulouse, 31059 Cedex 9, France

Location

Local Institution - 604

Dresden, 01307, Germany

Location

Universitatsklinikum Carl Gustav Carus

Dresden, 01307, Germany

Location

Local Institution - 603

Düsseldorf, 40479, Germany

Location

Marien Hospital

Düsseldorf, 40479, Germany

Location

Universitatsklinikum Essen

Essen, 45122, Germany

Location

Klinikum der Johann Wolfgang Goethe Universitat

Frankfurt am Main, 60590, Germany

Location

Universitatsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Medizinische Hochschule HannoverZentrum Innere Medizin

Hanover, 30625, Germany

Location

Universitatsklinikum Leipzig

Leipzig, 04103, Germany

Location

Klinikum der LMU Campus Grosshadern

München, 1307, Germany

Location

Local Institution - 605

München, 1307, Germany

Location

Klinikum rechts der Isar der TU Munchen

München, 81675, Germany

Location

Universitatsklinikum Ulm

Ulm, 89081, Germany

Location

AO Spedali Civili di Brescia

Brecia, 25123, Italy

Location

Azienda Ospedaliero-Universitaria Careggi

Florence, 50134, Italy

Location

Ospedale Niguarda Milano

Milan, 20162, Italy

Location

Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello

Palermo, 33100, Italy

Location

I.R.C.C.S. Policlinico San Matteo - Universita di Pavia

Pavia, 27100, Italy

Location

Local Institution - 302

Pavia, 27100, Italy

Location

Azienda Ospedaliera Bianchi-Melacrino-Morelli

Roma, 133, Italy

Location

Local Institution - 303

Roma, 133, Italy

Location

Policlinico Agostino Gemelli - Istituto di Ematologia

Roma, 89100, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Tor Vergata

Rome, 133, Italy

Location

Local Institution - 304

Rome, 133, Italy

Location

Azienda Ospedaliero-Universitaria Santa Maria della Misericordia die Udine

Udine, 30174, Italy

Location

Universita degli Studi dell'Insubria - Ospedale di Circolo e Fondazione Macchi - Varese

Varese, 21100, Italy

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

Oddzial Hematologii Onkologicznej Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologicz

Brzozów, 36-200, Poland

Location

Katedra i Klinika Hematologii i Transplantologii Uniwersyteckie Centrum Kliniczne

Gdansk, 80-211, Poland

Location

Samodzielny Publiczny Szpital Kliniczny nr 1 Klinika Hematoonkologii i Transplantacji Szpiku

Lubin, 20-081, Poland

Location

Oddzial Hematologii Samodzielny Publiczny Zaklad Opieki Zdrowotnej MSW

Olsztyn, 10-228, Poland

Location

Klinika Hematologii Nowotworow Krwi i Transplantacji Szpiku

Wroclaw, 50-367, Poland

Location

Hospitais da Universidade de Coimbra

Coimbra, 3000-076, Portugal

Location

Instituto Portugues de Oncologia de Lisboa Francisco Gentil EPE

Lisbon, 1099-023, Portugal

Location

Ipo Instituto Portugues De Oncologia Porto

Porto, 4200-072, Portugal

Location

Local Institution - 502

Porto, 4200-072, Portugal

Location

Hospital de Sao Joao

Porto, 4200, Portugal

Location

Hospital Universitario Vall D hebron

Barcelona, 28040, Spain

Location

Hospital Clinic I Provincial de Barcelona

Barcelona, 8036, Spain

Location

Complejo Hospitalario San Pedro de Alcantara

Cáceres, 10003, Spain

Location

Hospital Universitario La Princesa

Madrid, 28006, Spain

Location

Hospital Gregorio Maranon

Madrid, 37007, Spain

Location

Local Institution - 555

Madrid, 37007, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, 29010, Spain

Location

Hospital Son Llatzer

Palma de Mallorca, 7198, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Virgen del Rocio

Seville, 41013, Spain

Location

Hospital Universitario La Fe

Valencia, 46009, Spain

Location

Local Institution - 559

Valencia, 46009, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

Location

University Hospital Birmingham

Birmingham, B15 2TH, United Kingdom

Location

St James University Hospital

Leeds, LS1 3EX, United Kingdom

Location

St Bartholomews Hospital

London, EC1 7BE, United Kingdom

Location

Kings College Hospital

London, SE5 9RS, United Kingdom

Location

University College London Hospital

London Bloomsbury, WC1E 6AU, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Local Institution - 453

Oxford, OX3 9DU, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (4)

• Bewersdorf JP, Hasle V, Shallis RM, Thompson E, Lopes de Menezes D, Rose S, Boss I, Mendez L, Podoltsev N, Stahl M, Kewan T, Halene S, Haferlach T, Fox BA, Zeidan AM. Integrated Immune Landscape Analysis of RNA Splicing Factor-Mutant AML and Higher risk MDS Treated with Azacitidine +/- Durvalumab. Ther Adv Hematol. 2025 Jun 21;16:20406207251347344. doi: 10.1177/20406207251347344. eCollection 2025.

  PMID: 40546817 DERIVED

• Zeidan AM, Bewersdorf JP, Hasle V, Shallis RM, Thompson E, de Menezes DL, Rose S, Boss I, Halene S, Haferlach T, Fox BA. Integrated genetic, epigenetic, and immune landscape of TP53 mutant AML and higher risk MDS treated with azacitidine. Ther Adv Hematol. 2024 Jun 15;15:20406207241257904. doi: 10.1177/20406207241257904. eCollection 2024.

  PMID: 38883163 DERIVED

• Zeidan AM, Boss I, Beach CL, Copeland WB, Thompson E, Fox BA, Hasle VE, Ogasawara K, Cavenagh J, Silverman LR, Voso MT, Hellmann A, Tormo M, O'Connor T, Previtali A, Rose S, Garcia-Manero G. A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for higher-risk myelodysplastic syndromes. Blood Adv. 2022 Apr 12;6(7):2207-2218. doi: 10.1182/bloodadvances.2021005487.

  PMID: 34972214 DERIVED

• Zeidan AM, Boss I, Beach CL, Copeland WB, Thompson E, Fox BA, Hasle VE, Hellmann A, Taussig DC, Tormo M, Voso MT, Cavenagh J, O'Connor T, Previtali A, Rose S, Silverman LR. A randomized phase 2 trial of azacitidine with or without durvalumab as first-line therapy for older patients with AML. Blood Adv. 2022 Apr 12;6(7):2219-2229. doi: 10.1182/bloodadvances.2021006138.

  PMID: 34933333 DERIVED

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Azacitidine; durvalumab

Condition Hierarchy (Ancestors)

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

Limitations and Caveats

Protocol Amendment 03 was introduced on 05 Mar 2019. At the Investigator's discretion, participants meeting all the continuation criteria were eligible to enter the optional extension phase to continue to benefit from treatment with subcutaneous azacitidine and/or durvalumab. Participants started the extension phase at the time of their next regularly scheduled dosing cycle for study drug azacitidine or azacitidine and durvalumab.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• CL Beach, Pharm D

  Celgene Corporation

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2016
• First Posted: May 18, 2016
• Study Start: June 3, 2016
• Primary Completion: December 31, 2018
• Study Completion: December 27, 2021
• Last Updated: February 28, 2023
• Results First Posted: May 4, 2020

Record last verified: 2023-02

Locations

ES (13); CA (6); BE (6); FR (13); US (12); AU (7); NL (1); PL (5); IT (13); DE (13); PT (5); GB (9)