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

• Sponsor: Celgene (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02281084
• Collaborator: (none)
• Enrollment: 65
• Locations: 66
• Arms: 2
• Anticipated Duration (Months): 89.5
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: Oral Azacitidine; Drug: Durvalumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jul 6, 2015
• Actual Primary Completion Date: Jun 19, 2019
• Anticipated Study Completion Date: Dec 19, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Monotherapy: Oral Azacitidine 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; 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.; Other Names: CC-486
Experimental: Combination Therapy: Oral Azacitidine and Durvalumab 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; 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.; Other Names: CC-486 ; Drug: Durvalumab; Durvalumab 1500 mg by IV infusion on Day 1 of each 28 day treatment cycle.; Other Names: Imfinzi MEDI4736

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate Based on the Modified International Working Group (IWG) 2006 Response Criteria for Myelodysplastic Syndrome (MDS) [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]

   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)

Secondary Outcome Measures

1. Kaplan-Meier Estimate of Overall Survival [From day 1 of study drug to the data cut off date of 19 June 2019; median follow-up for OS = 15.96 and 8.35 months respectively in the SD and PD oral AZA alone arms and 13.48 and 13.33 months in the SD and PD combination arms]

   Overall survival (OS) was defined as the time from randomization to death from any cause, and was calculated using date of first dose and date of death, or date of last follow-up for censored subjects. All participants were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study termination. Participants who dropped out or were alive at study termination (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate.

2. 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]

   Time to onset of first response was defined as the time between the date of first investigational product (IP) dose and the earliest date any response (CR, PR, mCR, or HI) was first observed. Participants who did not achieve any defined response during the treatment period were censored at the date of treatment discontinuation, disease progression, or death, whichever occurred first. Best response is the best recorded response or treatment outcome from the start of the study treatment until the end of the study treatment taking into account the requirements for confirmation of response.

3. 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]

   Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.

4. 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]

   Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.

5. Kaplan-Meier Estimate of Progression Free Survival (PFS) [From day 1 of study drug to the data cut off date of 19 June 2019; median follow-up for OS = 15.96 and 8.35 months respectively in the SD/ PD oral AZA arms and 13.48 and 13.33 months in the SD/PD oral AZA and Durva arms]

   Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD), relapse, or death due to any cause during or after the treatment period, whichever occurred first, according to IWG 2006 response criteria for MDS. Participants who were still alive and progression-free were censored at the date of their last response assessment. Progressive disease is defined as follows: - an increase in BM blasts relative to nadir: •If nadir less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts •If nadir 5% - 10% blasts: ≥ 50% increase in blasts to > 10% blasts •If nadir 10% - 20% blasts: ≥ 50% increase in blasts to > 20% blasts •If nadir 20% - 30% blasts: ≥ 50% increase in blasts to > 30% blasts And any of the following: •At least 50% decrement from maximum remission/response levels in granulocytes or platelets •Reduction in Hgb concentration by ≥ 2 g/dL •Transfusion dependence

6. Percentage of Participants With Progressive Disease at Baseline Who Achieved Stable Disease [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]

   A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.

7. Kaplan-Meier Estimate of Onset to Achieve Stable Disease [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]

   A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.

8. Kaplan-Meier Estimate of Duration of Stable Disease [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]

   The duration of stable disease was defined as the time between any two observations of objective disease progression (modified IWG criteria), starting from the first day of dosing with IP. Participants who maintained stable disease through the end of the treatment period were censored at the date of study termination.

9. Percentage of Participants Who Progressed to Acute Myelogenous Leukemia (AML) [From Day 1 of study drug up to the data cut off date of 19 June 2019; median follow up time for AML progression = 11.59 and 5.65 months respectively in the SD and PD arms for oral AZA and 6.21 months for SD/PD in the combination arm.]

   For all participants who received at least one dose of study drug, continuous monitoring for progression to AML occurred in the post treatment follow up period.

10. Kaplan-Meier Estimate of Time to Progression to AML [From Day 1 of study drug up to the data cut off date of 19 June 2019; median follow up time for AML progression = 11.59 and 5.65 months respectively in the SD and PD arms for oral AZA and 6.21 months for SD/PD in the combination arm.]

    Time to AML progression was defined as the time from the date of first dose of IP until the date the participant had documented progression to AML.

11. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [From first dose of IP until 28 days after final oral AZA dose, 90 days after final durva dose and/or treatment stopped; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively; 1.84 months for AZA and Durva SD/PD arms]

    TEAEs were defined as AEs occurring or worsening on or after the date of the first dose of oral aza or durva and within 28 days after last dose of oral aza or 90 days after last dose of durva A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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:

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

1. 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

1. 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).

2. 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 (

3. Have an eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2

4. Females subjects of childbearing potential (FCBP)1 may participate, providing they meet the following conditions:

5. 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.

6. 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

7. 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.

1. Male subjects must:

2. Male subjects must:

3. 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.

4. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.

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

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

7. 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:

2. 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)

3. ≥100% increase in WBC count (myeloid cell line and monocyte series) within the 8-week period leading to Cycle 1, Day 1

4. 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.

5. Prior allogeneic stem cell transplant

6. Prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative at any time in the subject's prior history

7. 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

8. Ongoing medically significant adverse events from previous treatment, regardless of the time period

9. Use of any of the following within 28 days prior to the first dose of IP:

10. thrombopoiesis-stimulating agents ([TSAs]; eg, Romiplostim, Eltrombopag, Interleukin-11)

11. ESAs (Erythropoiesis stimulating agent) and other RBC hematopoietic growth factors (eg, interleukin-3)

12. hydroxyurea

13. 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

14. 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

15. 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:

16. Basal or squamous cell carcinoma of the skin

17. Carcinoma in situ of the cervix

18. Carcinoma in situ of the breast

19. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)

20. Significant active cardiac disease within the previous 6 months, including:

21. New York Heart Association (NYHA) class IV congestive heart failure;

22. Unstable angina or angina requiring surgical or medical intervention; and/or

23. Myocardial infarction

24. 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)

25. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection

26. Any of the following laboratory abnormalities:

27. 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)

28. 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

29. Serum creatinine > 2.5 x ULN (upper limit of normal)

30. Absolute WBC (white blood cell) count ≥ 20 x 109/L

31. Known or suspected hypersensitivity to azacitidine, mannitol, its constituents, or to any other humanized monoclonal antibody

32. 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

33. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

34. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study

35. Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than MDS, associated with anemia

36. 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

37. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS leukemia

38. 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:

39. Subjects with vitiligo or alopecia;

40. Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for ≥ 3 months; or

41. Subjects with psoriasis not requiring systemic treatment

42. History of primary immunodeficiency

43. Active myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Local Institution - 113	New Haven	Connecticut	United States	06520
2	Yale University	New Haven	Connecticut	United States	06520
3	University of Miami Miller School of Medicine	Miami	Florida	United States	33136
4	H Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
5	University of Chicago Medicine	Chicago	Illinois	United States	60637
6	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426-3558
7	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
8	James Graham Brown Cancer Center	Louisville	Kentucky	United States	40202
9	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
10	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	Hillman Cancer Institute at UPMC	Pittsburgh	Pennsylvania	United States	15232
13	University of Texas- MD Anderson	Houston	Texas	United States	77030
14	Cancer Care Centers of South Texas - HOAST	San Antonio	Texas	United States	78229
15	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
16	Westmead Hospital	Westmead	New South Wales	Australia	2145
17	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
18	Monash Medical Centre	Clayton	Victoria	Australia	3168
19	Cabrini Hospital	Malvern	Victoria	Australia	3144
20	Local Institution - 405	Malvern	Victoria	Australia	3144
21	Royal Brisbane and Women's Hospital	Herston		Australia	4029
22	Royal Perth Hospital	Perth		Australia	6000
23	Universitair Ziekenhuis Brussel	Brussel		Belgium	1090
24	Hopital Erasme	Bruxelles		Belgium	1070
25	Centre Hospitalier Universitaire de Liege	Liège		Belgium	4000
26	Clinique Saint-Pierre	Ottignies		Belgium	1340
27	Institut Paoli Calmettes	Marseille Cedex 9		France	13273
28	Hopital Saint-Louis	Paris		France	75010
29	Local Institution - 201	Paris		France	75010
30	CHU Purpan	Toulouse		France	31059
31	Local Institution - 500	Dresden		Germany	D-01307
32	Universitatsklinikum Carl Gustav Carus an der TU Dresden	Dresden		Germany	D-01307
33	Local Institution - 502	Dusseldorf		Germany	40479
34	Marien Hospital	Dusseldorf		Germany	40479
35	Universitatsklinikum Freiburg	Freiburg		Germany	79106
36	Universitatsklinikum Halle Saale	Halle		Germany	06120
37	Universitatsklinikum Leipzig	Leipzig		Germany	04103
38	Medizinische Klinik III Klinikum der Universität München-Großhadern	München		Germany	81377
39	Azienda Ospedaliera Santi Antonio Biagio E Cesare Arrigo	Allessandria		Italy	15100
40	Azienda Ospedaliera Universitaria Policlinico Sant Orsola Malpighi	Bologna		Italy	40138
41	Azienda Ospedaliero-Universitaria Careggi	Firenze		Italy	50134
42	Ospedale San Raffaele S.r.l.	Milano		Italy	20132
43	Azienda Ospedaliera Sant Andrea	Roma		Italy	00189
44	Local Institution - 603	Roma		Italy	00189
45	Zaklad Opieki Zdrowotnej MSW z Warminsko-Mazurskim Centrum Onkologii	Olsztyn		Poland	10-228
46	MTZ Clinical Research Sp. z o.o.	Warszawa		Poland	02-106
47	Uniwersytecki Szpital Kliniczny	Wroclaw		Poland	50-367
48	Institut Calatà d'Oncologia, L'Hospitalet	Barcelona		Spain	08907
49	Local Institution - 306	Barcelona		Spain	08907
50	Hospital Universitari Vall d'Hebron	Barcelona		Spain	8035
51	Hospital Virgenes de las Nieves	Granada		Spain	18014
52	Hospital General Gregorio Maranon	Madrid		Spain	28009
53	Hospital Universitario Virgen De La Victoria	Malaga		Spain	29010
54	Hospital Central de Asturias	Oviedo		Spain	33006
55	Hospital Universitario de Salamanca	Salamanca		Spain	37007
56	Hospital Universitario Virgen Del Rocio	Sevilla		Spain	41013
57	CEIC Hospital Universitario La Fe	Valencia		Spain	46009
58	United Lincolnshire Hospitals NHS Trust	Boston		United Kingdom	PE21 9QS
59	Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
60	Broomfield Hospital	Chelmsford		United Kingdom	CM17ET
61	Saint James University Hospital	Leeds		United Kingdom	LS1 3EX
62	King's College HospitalSchool of Medicine	London		United Kingdom	SE5 9RS
63	Hammersmith Hospital	London		United Kingdom	W12 0HS
64	University College London	London		United Kingdom	WC1E 6BT
65	Northwick Park Hospital	Middlesex		United Kingdom	HA1 3UJ
66	Southampton General Hospital	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

• Study Protocol - Jun 17, 2019
• Statistical Analysis Plan - Sep 8, 2015

More Information

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT02281084
• Other Study ID Numbers: CC-486-MDS-006; 2014-002675-29
• First Posted: Nov 2, 2014
• Last Update Posted: Aug 23, 2022
• Last Verified: Aug 1, 2022

• Keywords provided by Celgene: 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
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Azacitidine; Durvalumab

Study Results

Participant Flow

Recruitment Details	Participants were randomized at 33 sites globally. The sites were located in: Australia (3), Europe (18) and the United States (12). Results are reported as of the data cut-off date of 19 June 2019.
Pre-assignment Detail	Participants were eligible who did not respond to an adequate course of therapy with an injectable hypomethylating agent (iHMA - azacitidine or decitabine) or were unable to tolerate an iHMA following at least 3 months of attempted treatment.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Period Title: Overall Study
STARTED	32	22	6	5
COMPLETED	10	4	2	0
NOT COMPLETED	22	18	4	5

Baseline Characteristics

Arm/Group Title	Progressive Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Stable Disease (SD) Cohort: Oral Azacitidine	Total
Arm/Group Description	Participants received 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 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants were given 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.	Total of all reporting groups
Overall Participants	32	22	6	5	65
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.9 (7.62)	75.1 (7.56)	70.0 (7.21)	72.4 (5.55)	73.9 (7.42)
Sex: Female, Male (Count of Participants)
Female	12 37.5%	7 31.8%	0 0%	0 0%	19 29.2%
Male	20 62.5%	15 68.2%	6 100%	5 100%	46 70.8%
Race/Ethnicity, Customized (Count of Participants)
White	28 87.5%	18 81.8%	6 100%	5 100%	57 87.7%
Black	0 0%	1 4.5%	0 0%	0 0%	1 1.5%
Asian	1 3.1%	1 4.5%	0 0%	0 0%	2 3.1%
Native Hawaiian or Other Pacific Islander	0 0%	1 4.5%	0 0%	0 0%	1 1.5%
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Other	1 3.1%	1 4.5%	0 0%	0 0%	2 3.1%
Not Collected or Reported	2 6.3%	0 0%	0 0%	0 0%	2 3.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	1 3.1%	1 4.5%	0 0%	2 40%	4 6.2%
Not Hispanic or Latino	30 93.8%	21 95.5%	6 100%	3 60%	60 92.3%
Unknown	1 3.1%	0 0%	0 0%	0 0%	1 1.5%
Myelodysplastic Syndrome (MDS) World Health Organization Classification 2008 (Count of Participants)
Refractory Anemia (RA) with Ringed Sideroblasts	1 3.1%	0 0%	0 0%	0 0%	1 1.5%
Refractory Cytopenia with Multilineage Dysplasia	11 34.4%	2 9.1%	1 16.7%	0 0%	14 21.5%
RA With Excess Blasts-1 (RAEB-1)	10 31.3%	6 27.3%	1 16.7%	2 40%	19 29.2%
RA With Excess Blasts-2 (RAEB-2)	8 25%	11 50%	4 66.7%	3 60%	26 40%
MDS Unclassified (MDS-U)	1 3.1%	3 13.6%	0 0%	0 0%	4 6.2%
MDS Associated with Isolated del (5q)	0 0%	0 0%	0 0%	0 0%	0 0%
Missing	1 3.1%	0 0%	0 0%	0 0%	1 1.5%
International Prognostic Scoring System Risk Classification (Count of Participants)
Low (0)	4 12.5%	2 9.1%	0 0%	0 0%	6 9.2%
Intermediate 1 (0.5-1.0)	12 37.5%	5 22.7%	1 16.7%	2 40%	20 30.8%
Intermediate (2) (1.0-2.0)	7 21.9%	7 31.8%	4 66.7%	2 40%	20 30.8%
High (2) (≥ 2.5)	8 25%	8 36.4%	1 16.7%	1 20%	18 27.7%
Unknown	1 3.1%	0 0%	0 0%	0 0%	1 1.5%
French-American-British (FAB) Classification (Count of Participants)
Refractory Anemia (RA)	6 18.8%	2 9.1%	0 0%	0 0%	8 12.3%
Refractory Anemia with Ringed Sideroblasts (RARS)	6 18.8%	1 4.5%	1 16.7%	0 0%	8 12.3%
Refractory Anemia with Excess Blasts (RAEB)	17 53.1%	16 72.7%	5 83.3%	4 80%	42 64.6%
RAEB in Transformation	2 6.3%	3 13.6%	0 0%	1 20%	6 9.2%
Chronic Myelomonocytic Leukemia (CMML)	0 0%	0 0%	0 0%	0 0%	0 0%
Missing	1 3.1%	0 0%	0 0%	0 0%	1 1.5%
Time Since Initial Diagnosis of MDS (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	26.79 (29.678)	26.97 (33.835)	40.20 (61.663)	23.51 (30.524)	27.84 (34.266)
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Count of Participants)
0 (Fully active)	5 15.6%	6 27.3%	3 50%	2 40%	16 24.6%
1 (Restricted but Ambulatory)	22 68.8%	13 59.1%	3 50%	3 60%	41 63.1%
2 (Ambulatory But Unable to Work)	5 15.6%	3 13.6%	0 0%	0 0%	8 12.3%
3 (Limited Self-Care)	0 0%	0 0%	0 0%	0 0%	0 0%
4 (Completely Disabled)	0 0%	0 0%	0 0%	0 0%	0 0%
5 (Death)	0 0%	0 0%	0 0%	0 0%	0 0%
Baseline Platelet Transfusion Status (Count of Participants)
Dependent	4 12.5%	5 22.7%	0 0%	1 20%	10 15.4%
Independent	25 78.1%	13 59.1%	6 100%	4 80%	48 73.8%
Other	3 9.4%	4 18.2%	0 0%	0 0%	7 10.8%
Baseline Red Blood Cell (RBC) Transfusion Status (Count of Participants)
Dependent	8 25%	7 31.8%	0 0%	2 40%	17 26.2%
Independent	8 25%	6 27.3%	3 50%	2 40%	19 29.2%
Other	16 50%	9 40.9%	3 50%	1 20%	29 44.6%
Average Red Blood Cell (RBC) Transfusion Requirement (units per 56 days) [Median (Full Range) ]
Median (Full Range) [units per 56 days]	4.00	2.50	1.00	4.00	3.00

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate Based on the Modified International Working Group (IWG) 2006 Response Criteria for Myelodysplastic Syndrome (MDS)
Description	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)
Time Frame	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

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population included all enrolled participants who received at least one dose of investigational product (IP).

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Number (95% Confidence Interval) [Percentage of Participants]	6.3 19.7%	4.5 20.5%	16.7 278.3%	0 0%

2. Secondary Outcome

Title	Kaplan-Meier Estimate of Overall Survival
Description	Overall survival (OS) was defined as the time from randomization to death from any cause, and was calculated using date of first dose and date of death, or date of last follow-up for censored subjects. All participants were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study termination. Participants who dropped out or were alive at study termination (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate.
Time Frame	From day 1 of study drug to the data cut off date of 19 June 2019; median follow-up for OS = 15.96 and 8.35 months respectively in the SD and PD oral AZA alone arms and 13.48 and 13.33 months in the SD and PD combination arms

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Median (95% Confidence Interval) [Months]	17.00	6.28	14.70	14.56

3. Secondary Outcome

Title	Kaplan Meier Estimate of Time to Onset of First and Best Response
Description	Time to onset of first response was defined as the time between the date of first investigational product (IP) dose and the earliest date any response (CR, PR, mCR, or HI) was first observed. Participants who did not achieve any defined response during the treatment period were censored at the date of treatment discontinuation, disease progression, or death, whichever occurred first. Best response is the best recorded response or treatment outcome from the start of the study treatment until the end of the study treatment taking into account the requirements for confirmation of response.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Onset of First Response	NA	11.97	NA	NA
Onset of Best Response	3.68	4.41	3.29	2.17

4. Secondary Outcome

Title	Kaplan Meier Estimate of Duration of First Response
Description	Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP; participants who achieved a response.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	3	1	6	5
Median (95% Confidence Interval) [Months]	9.24	NA	NA	NA

5. Secondary Outcome

Title	Kaplan Meier Estimate of Duration of Best Response
Description	Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP; participants who achieved a best response.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Median (95% Confidence Interval) [Months]	NA	NA	NA	NA

6. Secondary Outcome

Title	Kaplan-Meier Estimate of Progression Free Survival (PFS)
Description	Progression-free survival is defined as the time from randomization to the first documented progressive disease (PD), relapse, or death due to any cause during or after the treatment period, whichever occurred first, according to IWG 2006 response criteria for MDS. Participants who were still alive and progression-free were censored at the date of their last response assessment. Progressive disease is defined as follows: - an increase in BM blasts relative to nadir: •If nadir less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts •If nadir 5% - 10% blasts: ≥ 50% increase in blasts to > 10% blasts •If nadir 10% - 20% blasts: ≥ 50% increase in blasts to > 20% blasts •If nadir 20% - 30% blasts: ≥ 50% increase in blasts to > 30% blasts And any of the following: •At least 50% decrement from maximum remission/response levels in granulocytes or platelets •Reduction in Hgb concentration by ≥ 2 g/dL •Transfusion dependence
Time Frame	From day 1 of study drug to the data cut off date of 19 June 2019; median follow-up for OS = 15.96 and 8.35 months respectively in the SD/ PD oral AZA arms and 13.48 and 13.33 months in the SD/PD oral AZA and Durva arms

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Median (95% Confidence Interval) [Months]	14.86	6.28	14.70	12.10

7. Secondary Outcome

Title	Percentage of Participants With Progressive Disease at Baseline Who Achieved Stable Disease
Description	A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes participants who had progressive disease at baseline who achieved stable disease.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	0	22	0	5
Number [Percentage of Participants]	31.8 99.4%	20.0 90.9%

8. Secondary Outcome

Title	Kaplan-Meier Estimate of Onset to Achieve Stable Disease
Description	A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Includes all participants in the ITT population with progressive disease at baseline and achieved stable disease; those who didn't achieve SD or better were censored.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	0	22	0	5
Median (95% Confidence Interval) [Months]	NA	NA

9. Secondary Outcome

Title	Kaplan-Meier Estimate of Duration of Stable Disease
Description	The duration of stable disease was defined as the time between any two observations of objective disease progression (modified IWG criteria), starting from the first day of dosing with IP. Participants who maintained stable disease through the end of the treatment period were censored at the date of study termination.
Time Frame	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

Outcome Measure Data

Analysis Population Description

The population includes participants who achieved stable disease as their best response.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	0	5
Median (95% Confidence Interval) [Months]	NA	NA	NA

10. Secondary Outcome

Title	Percentage of Participants Who Progressed to Acute Myelogenous Leukemia (AML)
Description	For all participants who received at least one dose of study drug, continuous monitoring for progression to AML occurred in the post treatment follow up period.
Time Frame	From Day 1 of study drug up to the data cut off date of 19 June 2019; median follow up time for AML progression = 11.59 and 5.65 months respectively in the SD and PD arms for oral AZA and 6.21 months for SD/PD in the combination arm.

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of IP.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Number [Percentage of Participants]	28.1 87.8%	18.2 82.7%	16.7 278.3%	60.0 1200%

11. Secondary Outcome

Title	Kaplan-Meier Estimate of Time to Progression to AML
Description	Time to AML progression was defined as the time from the date of first dose of IP until the date the participant had documented progression to AML.
Time Frame	From Day 1 of study drug up to the data cut off date of 19 June 2019; median follow up time for AML progression = 11.59 and 5.65 months respectively in the SD and PD arms for oral AZA and 6.21 months for SD/PD in the combination arm.

Outcome Measure Data

Analysis Population Description

The ITT population included all enrolled participants who received at least one dose of investigational product (IP).

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
Median (95% Confidence Interval) [Months]	NA	NA	NA	6.21

12. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	TEAEs were defined as AEs occurring or worsening on or after the date of the first dose of oral aza or durva and within 28 days after last dose of oral aza or 90 days after last dose of durva A serious adverse event (SAE) is any: Death; Life-threatening event; Any inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital anomaly or birth defect; Any other important medical event The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
Time Frame	From first dose of IP until 28 days after final oral AZA dose, 90 days after final durva dose and/or treatment stopped; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively; 1.84 months for AZA and Durva SD/PD arms

Outcome Measure Data

Analysis Population Description

The safety population included all enrolled participants who received at least 1 dose of IP and had at least 1 post-dose safety assessment.

Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.	Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.	Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.	Participants received 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 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.
Measure Participants	32	22	6	5
≥ 1 TEAE	32 100%	22 100%	6 100%	5 100%
≥ 1 TEAE Related to (R/T) Oral Azacitidine (AZA)	28 87.5%	20 90.9%	6 100%	4 80%
≥ 1 TEAE R/T Durvalumab (Durva)	0 0%	0 0%	5 83.3%	4 80%
≥ 1 TEAE R/T Oral AZA or Durva	28 87.5%	20 90.9%	6 100%	4 80%
≥ 1 Serious TEAE	25 78.1%	15 68.2%	4 66.7%	5 100%
≥ 1 Serious TEAE R/T Oral AZA	4 12.5%	3 13.6%	2 33.3%	1 20%
≥ 1 Serious TEAE R/T Durva	0 0%	0 0%	1 16.7%	1 20%
≥ 1 Serious TEAE R/T Oral AZA or Durva	4 12.5%	3 13.6%	2 33.3%	1 20%
≥ 1 NCI CTC Grade (GR) 3 or 4 TEAE	32 100%	19 86.4%	5 83.3%	5 100%
≥ 1 NCI CTC GR 3 or 4 TEAE R/T Oral AZA	18 56.3%	10 45.5%	4 66.7%	3 60%
≥ 1 NCI CTC GR 3 or 4 TEAE R/T Durva	0 0%	0 0%	2 33.3%	2 40%
≥ 1 NCI CTC GR 3 or 4 TEAE R/T AZA or Durva	18 56.3%	10 45.5%	4 66.7%	3 60%
≥ 1 TEAE Leading to Death	4 12.5%	4 18.2%	2 33.3%	0 0%
≥ 1 TEAE Leading to Death R/T Oral AZA	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Death R/T Durva	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Death R/T AZA or Durva	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Dose Reduction of AZA	9 28.1%	8 36.4%	1 16.7%	0 0%
≥ 1 TEAE Leading to Reduction of Durva	0 0%	0 0%	0 0%	0 0%
≥ 1 TEAE Leading to Reduction of AZA or Durva	9 28.1%	8 36.4%	1 16.7%	0 0%
≥1 TEAE Leading to Interruption of AZA	21 65.6%	13 59.1%	3 50%	4 80%
≥1 TEAE Leading to Interruption of Durva	0 0%	0 0%	2 33.3%	0 0%
≥1 TEAE Leading to Interruption of AZA or Durva	21 65.6%	12 54.5%	3 50%	4 80%
≥ 1 TEAE Leading to Discontinuation (D/C) of AZA	15 46.9%	8 36.4%	4 66.7%	4 80%
≥ 1 TEAE Leading to D/C of Durva	0 0%	0 0%	3 50%	3 60%
≥ 1 TEAE Leading to D/C of AZA or Durva	15 46.9%	8 36.4%	4 66.7%	4 80%

Adverse Events

Time Frame	From the date of the first dose of study drug until 28 days after the last dose of CC-486, 90 days after the last dose of durvalumab, or until the treatment discontinuation visit, whichever was later and those SAEs known to the investigator at any time thereafter that were suspected of being related to IP.
Adverse Event Reporting Description	Median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively; 1.84 months for AZA and Durva SD/PD arms
Arm/Group Title	Stable Disease (SD) Cohort: Oral Azacitidine		Progressive Disease (PD) Cohort: Oral Azacitidine		Stable Disease Cohort: Oral Azacitidine and Durvalumab		Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Arm/Group Description	Participants were given 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.		Participants were given oral azacitidine 100 mg, 150mg, or 200mg tablets 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.		Participants received 100 mg oral azacitidine (AZA) tablets BID on days 1 to 14 or days 1 to 21 of each 28-day treatment cycle and durvalumab (Durva) 1500 mg by intravenous 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.		Participants received 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 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.
All Cause Mortality
	Stable Disease (SD) Cohort: Oral Azacitidine		Progressive Disease (PD) Cohort: Oral Azacitidine		Stable Disease Cohort: Oral Azacitidine and Durvalumab		Progressive Disease Cohort: Oral Azacitidine and Durvalumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/32 (62.5%)		16/22 (72.7%)		3/6 (50%)		5/5 (100%)
Serious Adverse Events
	Stable Disease (SD) Cohort: Oral Azacitidine		Progressive Disease (PD) Cohort: Oral Azacitidine		Stable Disease Cohort: Oral Azacitidine and Durvalumab		Progressive Disease Cohort: Oral Azacitidine and Durvalumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/32 (78.1%)		15/22 (68.2%)		4/6 (66.7%)		5/5 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	2/32 (6.3%)		1/22 (4.5%)		2/6 (33.3%)		0/5 (0%)
Hyperleukocytosis	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Leukocytosis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Thrombocytopenia	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Cardiac disorders
Myocardial infarction	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Gastrointestinal disorders
Constipation	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Diarrhoea	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Haematemesis	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Intestinal ischaemia	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Nausea	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Rectal haemorrhage	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
General disorders
Death	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
General physical health deterioration	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Oedema peripheral	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pyrexia	2/32 (6.3%)		0/22 (0%)		1/6 (16.7%)		2/5 (40%)
Hepatobiliary disorders
Autoimmune hepatitis	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Hepatitis	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Infections and infestations
Appendicitis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Arthritis infective	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Bacteraemia	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Bacterial sepsis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Cellulitis	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Cellulitis gangrenous	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Clostridium difficile colitis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Diverticulitis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Fungaemia	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Gastroenteritis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Gastroenteritis norovirus	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Lower respiratory tract infection	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Neutropenic sepsis	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Oral herpes	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pneumonia	8/32 (25%)		2/22 (9.1%)		0/6 (0%)		2/5 (40%)
Pseudomonal sepsis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Sepsis	2/32 (6.3%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Serratia bacteraemia	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Skin infection	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Upper respiratory tract infection	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Urinary tract infection enterococcal	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Femur fracture	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Investigations
Ejection fraction decreased	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
White blood cell count increased	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Failure to thrive	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Tumour lysis syndrome	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Bone pain	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Joint effusion	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Myositis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Neck pain	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Glioma	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Sarcoma	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Transformation to acute myeloid leukaemia	8/32 (25%)		3/22 (13.6%)		1/6 (16.7%)		3/5 (60%)
Nervous system disorders
Ataxia	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Dementia	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Psychiatric disorders
Confusional state	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Renal and urinary disorders
Acute kidney injury	1/32 (3.1%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Haematuria	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Urinary retention	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pneumonia aspiration	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pulmonary oedema	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Respiratory distress	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Respiratory failure	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Erythema	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pyoderma gangrenosum	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Stable Disease (SD) Cohort: Oral Azacitidine		Progressive Disease (PD) Cohort: Oral Azacitidine		Stable Disease Cohort: Oral Azacitidine and Durvalumab		Progressive Disease Cohort: Oral Azacitidine and Durvalumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/32 (100%)		22/22 (100%)		6/6 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Anaemia	11/32 (34.4%)		9/22 (40.9%)		1/6 (16.7%)		3/5 (60%)
Febrile neutropenia	3/32 (9.4%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Neutropenia	12/32 (37.5%)		6/22 (27.3%)		1/6 (16.7%)		2/5 (40%)
Thrombocytopenia	6/32 (18.8%)		5/22 (22.7%)		1/6 (16.7%)		4/5 (80%)
Cardiac disorders
Atrial fibrillation	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		2/5 (40%)
Pericardial effusion	0/32 (0%)		0/22 (0%)		0/6 (0%)		2/5 (40%)
Sinus bradycardia	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Sinus tachycardia	0/32 (0%)		0/22 (0%)		0/6 (0%)		2/5 (40%)
Tachycardia	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Tricuspid valve disease	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Ear and labyrinth disorders
Ear pain	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Hypoacusis	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Vertigo positional	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Endocrine disorders
Hypothyroidism	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Eye disorders
Conjunctival haemorrhage	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Gastrointestinal disorders
Abdominal distension	3/32 (9.4%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Abdominal pain	3/32 (9.4%)		2/22 (9.1%)		2/6 (33.3%)		1/5 (20%)
Abdominal pain upper	3/32 (9.4%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Constipation	12/32 (37.5%)		9/22 (40.9%)		1/6 (16.7%)		2/5 (40%)
Diarrhoea	20/32 (62.5%)		11/22 (50%)		4/6 (66.7%)		2/5 (40%)
Dry mouth	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		1/5 (20%)
Duodenogastric reflux	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Dyspepsia	1/32 (3.1%)		3/22 (13.6%)		2/6 (33.3%)		1/5 (20%)
Dysphagia	2/32 (6.3%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Flatulence	3/32 (9.4%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Gastrointestinal haemorrhage	0/32 (0%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Gastrooesophageal reflux disease	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Gingival bleeding	2/32 (6.3%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Haemorrhoids	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Mouth haemorrhage	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		2/5 (40%)
Nausea	24/32 (75%)		12/22 (54.5%)		2/6 (33.3%)		2/5 (40%)
Oral mucosa haematoma	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Perianal erythema	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Periodontal disease	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Stomatitis	4/32 (12.5%)		3/22 (13.6%)		1/6 (16.7%)		1/5 (20%)
Vomiting	18/32 (56.3%)		11/22 (50%)		2/6 (33.3%)		3/5 (60%)
General disorders
Asthenia	9/32 (28.1%)		4/22 (18.2%)		0/6 (0%)		0/5 (0%)
Catheter site erythema	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Chills	1/32 (3.1%)		0/22 (0%)		1/6 (16.7%)		1/5 (20%)
Fatigue	10/32 (31.3%)		6/22 (27.3%)		2/6 (33.3%)		4/5 (80%)
Generalised oedema	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Oedema peripheral	6/32 (18.8%)		2/22 (9.1%)		1/6 (16.7%)		3/5 (60%)
Pyrexia	7/32 (21.9%)		3/22 (13.6%)		1/6 (16.7%)		1/5 (20%)
Immune system disorders
Haemophagocytic lymphohistiocytosis	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Infections and infestations
Cellulitis	2/32 (6.3%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Diverticulitis	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Folliculitis	0/32 (0%)		3/22 (13.6%)		0/6 (0%)		0/5 (0%)
Nasopharyngitis	2/32 (6.3%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Oral candidiasis	3/32 (9.4%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Oral herpes	4/32 (12.5%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Pneumonia	3/32 (9.4%)		2/22 (9.1%)		0/6 (0%)		2/5 (40%)
Rash pustular	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Staphylococcal infection	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Upper respiratory tract infection	6/32 (18.8%)		2/22 (9.1%)		1/6 (16.7%)		0/5 (0%)
Urinary tract infection	3/32 (9.4%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Injury, poisoning and procedural complications
Contusion	5/32 (15.6%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Fall	5/32 (15.6%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Skin wound	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Spinal compression fracture	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Transfusion reaction	1/32 (3.1%)		2/22 (9.1%)		0/6 (0%)		1/5 (20%)
Investigations
Alanine aminotransferase increased	2/32 (6.3%)		4/22 (18.2%)		0/6 (0%)		1/5 (20%)
Aspartate aminotransferase increased	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Blood alkaline phosphatase increased	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Blood bilirubin increased	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Blood creatinine increased	3/32 (9.4%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Cardiac murmur	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Electrocardiogram QT prolonged	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Platelet count decreased	0/32 (0%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Urine output decreased	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Weight decreased	10/32 (31.3%)		6/22 (27.3%)		0/6 (0%)		0/5 (0%)
White blood cell count increased	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Decreased appetite	15/32 (46.9%)		8/22 (36.4%)		1/6 (16.7%)		2/5 (40%)
Dehydration	2/32 (6.3%)		1/22 (4.5%)		1/6 (16.7%)		0/5 (0%)
Gout	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Hyperglycaemia	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Hyperkalaemia	1/32 (3.1%)		3/22 (13.6%)		0/6 (0%)		0/5 (0%)
Hyperphosphataemia	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Hyperuricaemia	0/32 (0%)		2/22 (9.1%)		1/6 (16.7%)		1/5 (20%)
Hypoalbuminaemia	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Hypocalcaemia	2/32 (6.3%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Hypokalaemia	4/32 (12.5%)		0/22 (0%)		0/6 (0%)		2/5 (40%)
Hypomagnesaemia	3/32 (9.4%)		2/22 (9.1%)		0/6 (0%)		1/5 (20%)
Hypophosphataemia	0/32 (0%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/32 (12.5%)		3/22 (13.6%)		0/6 (0%)		0/5 (0%)
Back pain	7/32 (21.9%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Muscle spasms	1/32 (3.1%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Muscular weakness	4/32 (12.5%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Myalgia	3/32 (9.4%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Polyarthritis	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Nervous system disorders
Dizziness	6/32 (18.8%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Dysgeusia	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Headache	4/32 (12.5%)		1/22 (4.5%)		1/6 (16.7%)		0/5 (0%)
Lethargy	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Somnolence	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Psychiatric disorders
Delirium	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Depression	0/32 (0%)		2/22 (9.1%)		0/6 (0%)		1/5 (20%)
Insomnia	5/32 (15.6%)		2/22 (9.1%)		0/6 (0%)		1/5 (20%)
Irritability	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Renal and urinary disorders
Acute kidney injury	1/32 (3.1%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Dysuria	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pollakiuria	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Renal cyst	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Renal disorder	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Urinary incontinence	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Urinary retention	2/32 (6.3%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Urinary tract obstruction	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Reproductive system and breast disorders
Oedema genital	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Penile pain	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	7/32 (21.9%)		4/22 (18.2%)		0/6 (0%)		1/5 (20%)
Dyspnoea	9/32 (28.1%)		4/22 (18.2%)		0/6 (0%)		0/5 (0%)
Dyspnoea exertional	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Epistaxis	3/32 (9.4%)		1/22 (4.5%)		0/6 (0%)		2/5 (40%)
Hypoxia	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Nasal congestion	1/32 (3.1%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Oropharyngeal pain	3/32 (9.4%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Pleural effusion	1/32 (3.1%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Productive cough	2/32 (6.3%)		2/22 (9.1%)		0/6 (0%)		0/5 (0%)
Pulmonary hypertension	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/32 (0%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Dermatitis bullous	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Erythema multiforme	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)
Night sweats	1/32 (3.1%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Petechiae	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pruritus	3/32 (9.4%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Pruritus generalised	2/32 (6.3%)		1/22 (4.5%)		0/6 (0%)		0/5 (0%)
Rash	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Rash maculo-papular	3/32 (9.4%)		1/22 (4.5%)		1/6 (16.7%)		1/5 (20%)
Urticaria	1/32 (3.1%)		0/22 (0%)		1/6 (16.7%)		0/5 (0%)
Vascular disorders
Haematoma	1/32 (3.1%)		1/22 (4.5%)		0/6 (0%)		1/5 (20%)
Hypertension	2/32 (6.3%)		0/22 (0%)		0/6 (0%)		0/5 (0%)
Hypotension	1/32 (3.1%)		1/22 (4.5%)		0/6 (0%)		3/5 (60%)
Thrombophlebitis superficial	0/32 (0%)		0/22 (0%)		0/6 (0%)		1/5 (20%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Results from a center cannot be submitted for publication before results of multicenter study are published unless it is > 1 year since study completion. Then, Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 additional days. Investigator must delete confidential information before submission and defer publication to permit patent applications.