Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes

NCT02281084 | Completed Phase 2 Results DMC

• 2 other identifiers: CC-486-MDS-0062014-002675-29
• Study Type: interventional
• Target: 65
• Locations: 10 countries
• Sites: 89

Brief Summary

Evaluate the safety and efficacy of oral azacitidne (CC-486) twice daily (BID) in subjects with myelodysplastic syndromes who failed to achieve an objective response post injectable hypomethylating agent (iHMA) treatment Reason for removing the combination arm: Due to difficulties with dose-finding, the durvalumab plus CC-486 combination arm was closed to enrollment. Extension: An Extension Phase (EP) has been added to allow subjects who are currently receiving oral azacitidine BID and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine until the subject meets the criteria for study discontinuation.

Conditions

Myelodysplastic Syndromes

Keywords

Keywords provided by Celgene:; myelodysplastic syndromes; MDS; azacitidine; oral azacitidine (CC-486); decitabine; intermediate-1; intermediate-2 and high risk myelodysplastic syndromes (MDS); proliferative chronic myelomonocytic leukemia (CMML); Chronic; iHMA (injectable hypomethylating agents); PD-L1

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate Based on the Modified International Working Group (IWG) 2006 Response Criteria for Myelodysplastic Syndrome (MDS)

  The overall response rate (ORR) was defined as the percentage of participants who achieved an objective response including: hematologic improvement (HI), partial remission (PR), complete remission (CR), or marrow complete remission (mCR). Hematologic response was defined as: • CR: ≤ 5% myeloblasts with normal maturation of all cell lines; peripheral blood (PB) shows: hemoglobin ≥11 g/dL, neutrophils ≥1.0x10\^9/L, platelets ≥100x10\^9/dL, blasts (0%) • PR: same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still \> 5%; cellularity and morphology not relevant • mCR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB, PB: if HI responses, noted in addition to mCR • HI: HI erythroid response (HI-E); HI neutrophil response (HI-N) ; HI platelet response (HI-P)

  Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

Secondary Outcomes (18)

• Kaplan-Meier Estimate of Overall Survival

  From first dose till death due to any cause (Up to 91 months)

• Kaplan Meier Estimate of Time to Onset of First and Best Response

  Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

• Kaplan Meier Estimate of Duration of First Response

  Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

• Kaplan Meier Estimate of Duration of Best Response

  Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

• Kaplan-Meier Estimate of Progression Free Survival (PFS)

  From first dose to the first documented progressive disease (PD), relapse, or death due to any cause (Up to 91 months)

Study Arms (2)

Monotherapy: Oral Azacitidine

EXPERIMENTAL

Oral azacitidine (AZA) 100 mg, 150 mg, or 200 mg tablets twice daily (BID) on days 1 to 21 of each 28-day treatment cycle. Participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred.

Drug: Oral Azacitidine

Combination Therapy: Oral Azacitidine and Durvalumab

EXPERIMENTAL

Oral Azacitidine 100 mg oral azacitidine tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab 1500 mg by intravenous (IV) infusion on day 1 of each 28-day treatment cycle; participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred.

Drug: Oral Azacitidine; Drug: Durvalumab

Interventions

Oral Azacitidine DRUG

Oral azacitidine (AZA) 100 mg, 150 mg, or 200 mg tablets twice daily (BID) on days 1 to 21 of each 28-day treatment cycle. Participants continued to receive their assigned study treatment unless disease progression, unacceptable toxicity, lost to follow-up or withdrawal by participant occurred.

Also known as: CC-486

Combination Therapy: Oral Azacitidine and Durvalumab; Monotherapy: Oral Azacitidine

Durvalumab DRUG

Durvalumab 1500 mg by IV infusion on Day 1 of each 28 day treatment cycle.

Also known as: Imfinzi, MEDI4736

Combination Therapy: Oral Azacitidine and Durvalumab

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, ≥ 18 years of age at the time of signing the informed consent document
• Documented diagnosis of MYELODYSPLASTIC SYNDROMES (MDS), classified according to FRENCH-AMERICAN BRITISH (FAB) classification criteria
• Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for MDS prior to beginning screening for this study. Adequate is defined as:
• having received at least 6 consecutive 4-week treatment cycles with azacitidine for injection, or
• having received at least 4 consecutive 6-week treatment cycles with decitabine (3-day regimen) or at least 6 consecutive 4-week treatment cycles with decitabine (5-day regimen), or
• having demonstrated inability to tolerate treatment with an injectable hypomethylating agent because of unacceptable drug-related toxicity after at least 3 months of attempted treatment: Three 28-day cycles of azacitidine for injection or decitabine 5-day regimen; two 42-day cycles of decitabine 3-day regimen.
• Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine. Those achieving an objective response to treatment regimen with an injectable hypomethylating agent (HMA) are excluded from participation in this study.
• Definitions of disease progression are modified from INTERNATIONAL WORKING GROUP (IWG) 2006 criteria and include:
• \- Pre-injectable hypomethylating agent baseline bone marrow myeloblasts:
• Less than 5%: ≥ 100% increase to ≥ 8% blasts
• \- Any clinical worsening from pre-injectable hypomethylating agents (HMA) baseline condition, including:
• <!-- -->
• sustained clinically-significant worsening (investigator's assessment) from baseline granulocyte, platelet, or hemoglobin values (≥ 2 values, separated by ≥ 2 weeks) - worsening granulocytes should be ≥ 50% decrease from pre-injectable HMA baseline value - worsening platelets should be ≥ 50% decrease from pre-injectable HMA baseline value (untransfused)
• worsening hemoglobin should be ≥ 1.5 g/dL decrease from preinjectable HMA baseline value in subjects not receiving RBC transfusions
• meaningful worsening in RBC or platelet transfusion requirement

You may not qualify if:

• Rapidly-progressing MDS defined as:
• Known clinically-significant doubling in marrow or per IP peripheral blood blast percentage (to ≥ 20%) in the 8-week period leading to the first dose of IP (Cycle 1, Day 1)
• ≥100% increase in WBC count (myeloid cell line and monocyte series) within the 8-week period leading to Cycle 1, Day 1
• Prior allogeneic stem cell transplant
• Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative at any time in the subject's prior history
• Prior or ongoing response (IWG 2006: HI, PR, CR, or marrow CR) to treatment with azacitidine for injection or decitabine, at any time in the subject's prior history, which includes relapsed disease
• Ongoing medically significant adverse events from previous treatment, regardless of the time period
• Use of any of the following within 28 days prior to the first dose of IP:
• thrombopoiesis-stimulating agents (\[TSAs\]; eg, Romiplostim, Eltrombopag, Interleukin-11)
• ESAs (Erythropoiesis stimulating agent) and other RBC hematopoietic growth factors (eg, interleukin-3)
• hydroxyurea
• Concurrent use of corticosteroids unless the subject is on a stable or decreasing dose for ≥ 1 week prior to enrollment for medical conditions other than MDS
• History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the IP and/or predispose the subject to an increased risk of gastrointestinal toxicity
• Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin

Sponsors & Collaborators

• Celgene: lead

Study Sites (89)

Local Institution - 113

New Haven, Connecticut, 06520, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33136, United States

Location

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

Local Institution - 104

Tampa, Florida, 33612, United States

Location

Local Institution - 111

Chicago, Illinois, 60637, United States

Location

University of Chicago Medicine

Chicago, Illinois, 60637, United States

Location

Ingalls Memorial Hospital

Harvey, Illinois, 60426-3558, United States

Location

Local Institution - 109

Harvey, Illinois, 60426-3558, United States

Location

Local Institution - 116

Iowa City, Iowa, 52242, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

James Graham Brown Cancer Center

Louisville, Kentucky, 40202, United States

Location

Local Institution - 103

Louisville, Kentucky, 40202, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Local Institution - 102

Hackensack, New Jersey, 07601, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Local Institution - 101

New York, New York, 10029, United States

Location

Local Institution - 110

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Hillman Cancer Institute at UPMC

Pittsburgh, Pennsylvania, 15232, United States

Location

University of Texas- MD Anderson

Houston, Texas, 77030, United States

Location

Cancer Care Centers of South Texas - HOAST

San Antonio, Texas, 78229, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Local Institution - 401

Adelaide, South Australia, 5000, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Local Institution - 400

Clayton, Victoria, 3168, Australia

Location

Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

Cabrini Hospital

Malvern, Victoria, 3144, Australia

Location

Local Institution - 405

Malvern, Victoria, 3144, Australia

Location

Royal Brisbane and Women's Hospital

Herston, 4029, Australia

Location

Royal Perth Hospital

Perth, 6000, Australia

Location

Hopital Erasme

Brussels, 1070, Belgium

Location

Local Institution - 802

Brussels, 1070, Belgium

Location

Local Institution - 801

Brussels, 1090, Belgium

Location

Universitair Ziekenhuis Brussel

Brussels, 1090, Belgium

Location

Centre Hospitalier Universitaire de Liege

Liège, 4000, Belgium

Location

Local Institution - 800

Liège, 4000, Belgium

Location

Clinique Saint-Pierre

Ottignies, 1340, Belgium

Location

Local Institution - UNK-004

Hamilton, Ontario, L8V1C3, Canada

Location

Institut Paoli Calmettes

Marseille, 13273, France

Location

Hopital Saint-Louis

Paris, 75010, France

Location

Local Institution - 201

Paris, 75010, France

Location

CHU Purpan

Toulouse, 31059, France

Location

Local Institution - 500

Dresden, D-01307, Germany

Location

Universitatsklinikum Carl Gustav Carus an der TU Dresden

Dresden, D-01307, Germany

Location

Local Institution - 502

Düsseldorf, 40479, Germany

Location

Marien Hospital

Düsseldorf, 40479, Germany

Location

Universitatsklinikum Freiburg

Freiburg im Breisgau, 79106, Germany

Location

Universitatsklinikum Halle Saale

Halle, 06120, Germany

Location

Universitatsklinikum Leipzig

Leipzig, 04103, Germany

Location

Medizinische Klinik III Klinikum der Universität München-Großhadern

München, 81377, Germany

Location

Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo

Allessandria, 15100, Italy

Location

Azienda Ospedaliera Universitaria Policlinico Sant Orsola Malpighi

Bologna, 40138, Italy

Location

Azienda Ospedaliero-Universitaria Careggi

Florence, 50134, Italy

Location

Local Institution - 601

Florence, 50134, Italy

Location

Ospedale San Raffaele S.r.l.

Milan, 20132, Italy

Location

Azienda Ospedaliera Sant Andrea

Roma, 00189, Italy

Location

Local Institution - 603

Roma, 00189, Italy

Location

Zaklad Opieki Zdrowotnej MSW z Warminsko-Mazurskim Centrum Onkologii

Olsztyn, 10-228, Poland

Location

Local Institution - 900

Warsaw, 02-106, Poland

Location

MTZ Clinical Research Sp. z o.o.

Warsaw, 02-106, Poland

Location

Uniwersytecki Szpital Kliniczny

Wroclaw, 50-367, Poland

Location

Institut Calatà d'Oncologia, L'Hospitalet

Barcelona, 08907, Spain

Location

Local Institution - 306

Barcelona, 08907, Spain

Location

Hospital Universitari Vall d'Hebron

Barcelona, 8035, Spain

Location

Hospital Virgenes de las Nieves

Granada, 18014, Spain

Location

Local Institution - 300

Granada, 18014, Spain

Location

Hospital General Gregorio Maranon

Madrid, 28009, Spain

Location

Local Institution - 307

Madrid, 28009, Spain

Location

Hospital Universitario Virgen De La Victoria

Málaga, 29010, Spain

Location

Hospital Central de Asturias

Oviedo, 33006, Spain

Location

Local Institution - 303

Oviedo, 33006, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Local Institution - 304

Salamanca, 37007, Spain

Location

Hospital Universitario Virgen Del Rocio

Seville, 41013, Spain

Location

Local Institution - 308

Seville, 41013, Spain

Location

CEIC Hospital Universitario La Fe

Valencia, 46009, Spain

Location

Local Institution - 701

Boston, PE21 9QS, United Kingdom

Location

United Lincolnshire Hospitals NHS Trust

Boston, PE21 9QS, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital

Cambridge, CB2 0QQ, United Kingdom

Location

Broomfield Hospital

Chelmsford, CM17ET, United Kingdom

Location

Saint James University Hospital

Leeds, LS1 3EX, United Kingdom

Location

King's College HospitalSchool of Medicine

London, SE5 9RS, United Kingdom

Location

Local Institution - 700

London, SE5 9RS, United Kingdom

Location

Hammersmith Hospital

London, W12 0HS, United Kingdom

Location

University College London

London, WC1E 6BT, United Kingdom

Location

Northwick Park Hospital

Middlesex, HA1 3UJ, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Myelodysplastic Syndromes; Bronchiolitis Obliterans Syndrome

Interventions

Azacitidine; cc-486; durvalumab

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System 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

Results Point of Contact

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

Clinical.Trials@bms.com

Please Email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  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
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 21, 2014
• First Posted: November 3, 2014
• Study Start: July 6, 2015
• Primary Completion: June 19, 2019
• Study Completion: September 14, 2023
• Last Updated: October 4, 2024
• Results First Posted: July 8, 2020

Record last verified: 2024-09

Locations

PL (4); ES (15); DE (8); GB (11); AU (9); US (23); BE (7); CA (1); IT (7); FR (4)