Clinical trial NCT02281084: Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes
Official title: A Phase 2, International, Multicenter, Randomized, Open-label, Parallel Group to Evaluate the Efficacy and Safety of Cc-486 (Oral Azacitidine) Alone in Combination With Durvalumab (MEDI4736) in Subjects With Myelodysplastic Syndromes Who Fail to Achieve an Objective Response to Treatment With Azacitidine for Injection or Decitabine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2014-11-02
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Male or female, ≥ 18 years of age at the time of signing the informed consent document
2. Documented diagnosis of MYELODYSPLASTIC SYNDROMES (MDS), classified according to FRENCH-AMERICAN BRITISH (FAB) classification criteria
3. 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.
4. 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:
   1. Less than 5%: ≥ 100% increase to ≥ 8% blasts
   2. ≥ 5%: ≥ 50% increase to ≥ 10% blasts Note: ≥ 30% blasts is considered acute myeloid leukemia (AML )per FAB classification. Subjects known to have ≥ 30% blasts are not eligible for inclusion in this study.recognizing eastern cooperative oncology group) limitations of blast cell quantification, Protocol will allow subjects with pre-enrollment bone marrow blast counts up to 33% on the screening bone marrow examination to be considered for inclusion. Assessment may be made according to local bone marrow examination to facilitate enrollment of eligible subjects into the treatment phase of the study.

      - Any clinical worsening from pre-injectable hypomethylating agents (HMA) baseline condition, including:

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   1. 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
   2. meaningful worsening in RBC or platelet transfusion requirement

      Definition of stable disease is based on modified IWG 2006 criteria:
      * Failure to achieve any objective response (CR - complete remission, PR - partial remissino, mCR - marrow complete remission, or HI - hematologic improvement), but no evidence of disease progression within the 8 weeks leading to the subject's first dose of investigational product (IP), Cycle 1, Day 1
5. Have the last dose of the prior treatment regimen injectable HMA - (azacitidine for injection or decitabine) not more than 16 weeks prior to screening for this study (date of informed consent signature).
6. No less than 3 weeks between the last dose of the prior treatment regimen injectable HMA - (azacitidine for injection or decitabine) and the planned date of first dose of IP (
7. Have an eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2
8. Females subjects of childbearing potential (FCBP)1 may participate, providing they meet the following conditions:

   1. Have two negative pregnancy tests as verified by the investigator prior to starting any 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 abstinence2 from heterosexual contact.
   2. Agree to practice true abstinence2 (which must be reviewed on a monthly basis and source documented) or agree to the use of highly effective methods of contraception from 28 days prior to starting azacitidine, and must agree to continue using such precautions while taking azacitidine (including dose interruptions) and for up to 90 days after the last dose of azacitidine. Cessation of contraception after this point should be discussed with a responsible physician
   3. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP.

Note that the screening serum pregnancy test can also be used as the test prior to starting IP if it is performed within the 72-hour timeframe.

9. Male subjects must:

1. Male subjects must:

   1. Either practice true abstinence2 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 child bearing 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 azacitidine.
2. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.

   10. Understand and voluntarily sign an informed consent document prior to any study-related assessments or procedures conducted.

   11. Be able to adhere to the study visit schedule and other protocol requirements.

   12. Understand and voluntarily sign a biomarker-specific component of the informed consent document prior to any study-related procedures conducted.

Extension Phase

At the Investigator's discretion and following confirmation of eligibility criteria below, subjects can enter the Extension Phase (EP):

* Subjects who have signed the informed consent for the EP of the study;
* Subjects receiving oral azacitidine and continuing in the treatment phase demonstrating clinical benefit as assessed by the Investigator are eligible to receive oral azacitidine in the EP;
* Subjects who do not meet any of the criteria for study discontinuation

Exclusion Criteria:

1. Rapidly-progressing MDS defined as:

   1. 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)
   2. ≥100% increase in WBC count (myeloid cell line and monocyte series) within the 8-week period leading to Cycle 1, Day 1
2. AML - FAB (FRENCH-AMERICAN-BRITISH) classification: ≥ 30% blasts in bone marrow). Subjects known to have ≥ 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to be considered for inclusion.
3. Prior allogeneic stem cell transplant
4. Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative at any time in the subject's prior history
5. 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
6. Ongoing medically significant adverse events from previous treatment, regardless of the time period
7. Use of any of the following within 28 days prior to the first dose of IP:

   1. thrombopoiesis-stimulating agents (\[TSAs\]; eg, Romiplostim, Eltrombopag, Interleukin-11)
   2. ESAs (Erythropoiesis stimulating agent) and other RBC hematopoietic growth factors (eg, interleukin-3)
   3. hydroxyurea
8. 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
9. 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
10. 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:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix
    3. Carcinoma in situ of the breast
    4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system)
11. Significant active cardiac disease within the previous 6 months, including:

    1. New York Heart Association (NYHA) class IV congestive heart failure;
    2. Unstable angina or angina requiring surgical or medical intervention; and/or
    3. Myocardial infarction
12. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
13. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection
14. Any of the following laboratory abnormalities:

    1. Serum Aspartate transaminase / Serum glutamic oxaloacetic transaminase (AST/SGOT) Alanine aminotransaminase / Serum glutamic pyruvate transaminase (ALT/SGPT) \> 2.5 x ULN (upper limit of normal)
    2. Serum total bilirubin \> 1.5 x upper limit of normal (ULN). Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of \> 2% with either a positive Coombs' test or over 50% of indirect bilirubin
    3. Serum creatinine \> 2.5 x ULN (upper limit of normal)
    4. Absolute WBC (white blood cell) count ≥ 20 x 109/L
15. Known or suspected hypersensitivity to azacitidine, mannitol, its constituents, or to any other humanized monoclonal antibody
16. Pregnant, planning to become pregnant starting from 28 days prior to receiving CC-486 throughout your participation in the study, and for at least 90 days following your last dose of study treatment, or breast-feeding females
17. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
18. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
19. Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than MDS, associated with anemia
20. Having received any prior MAb (monoclonal antibodies) against CTLA-4 (cytotoxic T lymphocyte-associated antigen), PD-1, or PD-L1 or having received other investigational monoclonalantibodies (MAbs) within 6 months
21. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS leukemia
22. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis, Crohn's disease\], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome \[granulomatosis with polyangiitis\]; myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

    1. Subjects with vitiligo or alopecia;
    2. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for ≥ 3 months; or
    3. Subjects with psoriasis not requiring systemic treatment
23. History of primary immunodeficiency
24. Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML)

Primary outcomes:
measure: Overall Response Rate Based on the Modified International Working Group (IWG) 2006 Response Criteria for Myelodysplastic Syndrome (MDS)
timeFrame: 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:
measure: Kaplan-Meier Estimate of Overall Survival
timeFrame: From first dose till death due to any cause (Up to 91 months)
measure: Kaplan Meier Estimate of Time to Onset of First and Best Response
timeFrame: 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
measure: Kaplan Meier Estimate of Duration of First Response
timeFrame: 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
measure: Kaplan Meier Estimate of Duration of Best Response
timeFrame: 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
measure: Kaplan-Meier Estimate of Progression Free Survival (PFS)
timeFrame: From first dose to the first documented progressive disease (PD), relapse, or death due to any cause (Up to 91 months)
measure: Percentage of Participants With Progressive Disease at Baseline Who Achieved Stable Disease
timeFrame: 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
measure: Kaplan-Meier Estimate of Onset to Achieve Stable Disease
timeFrame: 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
measure: Kaplan-Meier Estimate of Duration of Stable Disease
timeFrame: 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
measure: Percentage of Participants Who Progressed to Acute Myelogenous Leukemia (AML)
timeFrame: From first dose and until death, loss to follow-up, withdrawal of consent for further data collection (Up to 91 months)
measure: Kaplan-Meier Estimate of Time to Progression to AML
timeFrame: From first dose and until death, loss to follow-up, withdrawal of consent for further data collection (Up to 91 months)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose until 28 days after the last dose of CC-486 (90 days after the last dose of durvalumab) or the last follow up visit, whichever date is later (Up to 91 months)
measure: Serum Plasma Concentration of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Maximum Observed Concentration (Cmax) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Area Under Curve (AUC) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Time to Maximum Concentration (Tmax) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Terminal Half-life ( ½) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Clearance (CL/F) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
measure: Volume of Distribution (Vz/F) of Azacitidine and Durvalumab
timeFrame: Day 1, 8, 15 and 22
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Local Institution - 113
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Tampa
country: United States
facility: Local Institution - 104
state: Florida
city: Chicago
country: United States
facility: Local Institution - 111
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Harvey
country: United States
facility: Local Institution - 109
state: Illinois
city: Iowa City
country: United States
facility: Local Institution - 116
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: James Graham Brown Cancer Center
state: Kentucky
city: Louisville
country: United States
facility: Local Institution - 103
state: Kentucky
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center
state: New Jersey
city: Hackensack
country: United States
facility: Local Institution - 102
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Local Institution - 101
state: New York
city: Philadelphia
country: United States
facility: Local Institution - 110
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hillman Cancer Institute at UPMC
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas- MD Anderson
state: Texas
city: San Antonio
country: United States
facility: Cancer Care Centers of South Texas - HOAST
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Local Institution - 401
state: South Australia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Local Institution - 400
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Hospital
state: Victoria
city: Malvern
country: Australia
facility: Local Institution - 405
state: Victoria
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Brussel
country: Belgium
facility: Local Institution - 801
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Bruxelles
country: Belgium
facility: Hopital Erasme
city: Bruxelles
country: Belgium
facility: Local Institution - 802
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liege
city: Liège
country: Belgium
facility: Local Institution - 800
city: Ottignies
country: Belgium
facility: Clinique Saint-Pierre
city: Hamilton
country: Canada
facility: Local Institution - UNK-004
state: Ontario
city: Marseille Cedex 9
country: France
facility: Institut Paoli Calmettes
city: Paris
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: Local Institution - 201
city: Toulouse
country: France
facility: CHU Purpan
city: Dresden
country: Germany
facility: Local Institution - 500
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus an der TU Dresden
city: Dusseldorf
country: Germany
facility: Local Institution - 502
city: Dusseldorf
country: Germany
facility: Marien Hospital
city: Freiburg
country: Germany
facility: Universitatsklinikum Freiburg
city: Halle
country: Germany
facility: Universitatsklinikum Halle Saale
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
city: München
country: Germany
facility: Medizinische Klinik III Klinikum der Universität München-Großhadern
city: Allessandria
country: Italy
facility: Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo
city: Bologna
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Sant Orsola Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Firenze
country: Italy
facility: Local Institution - 601
city: Milano
country: Italy
facility: Ospedale San Raffaele S.r.l.
city: Roma
country: Italy
facility: Azienda Ospedaliera Sant Andrea
city: Roma
country: Italy
facility: Local Institution - 603
city: Olsztyn
country: Poland
facility: Zaklad Opieki Zdrowotnej MSW z Warminsko-Mazurskim Centrum Onkologii
city: Warszawa
country: Poland
facility: Local Institution - 900
city: Warszawa
country: Poland
facility: MTZ Clinical Research Sp. z o.o.
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny
city: Barcelona
country: Spain
facility: Institut Calatà d'Oncologia, L'Hospitalet
city: Barcelona
country: Spain
facility: Local Institution - 306
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Granada
country: Spain
facility: Hospital Virgenes de las Nieves
city: Granada
country: Spain
facility: Local Institution - 300
city: Madrid
country: Spain
facility: Hospital General Gregorio Maranon
city: Madrid
country: Spain
facility: Local Institution - 307
city: Malaga
country: Spain
facility: Hospital Universitario Virgen De La Victoria
city: Oviedo
country: Spain
facility: Hospital Central de Asturias
city: Oviedo
country: Spain
facility: Local Institution - 303
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Salamanca
country: Spain
facility: Local Institution - 304
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Del Rocio
city: Sevilla
country: Spain
facility: Local Institution - 308
city: Valencia
country: Spain
facility: CEIC Hospital Universitario La Fe
city: Boston
country: United Kingdom
facility: Local Institution - 701
city: Boston
country: United Kingdom
facility: United Lincolnshire Hospitals NHS Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
city: Leeds
country: United Kingdom
facility: Saint James University Hospital
city: London
country: United Kingdom
facility: King's College HospitalSchool of Medicine
city: London
country: United Kingdom
facility: Local Institution - 700
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: University College London
city: Middlesex
country: United Kingdom
facility: Northwick Park Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: