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Clinical Trial Results:
A Phase 2, International, Multicenter, Randomized, Open-label, Parallel Group Study to Evaluate the Efficacy and Safety of CC-486 (oral azacitidine) Alone and 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

Summary
EudraCT number	2014-002675-29
Trial protocol	FR GB BE ES DE PL IT
Global end of trial date	14 Sep 2023

Results information
Results version number	v1(current)
This version publication date	25 Sep 2024
First version publication date	25 Sep 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CC-486-MDS-006

ISRCTN number

US NCT number

NCT02281084

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium,

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

14 Sep 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Sep 2023

Was the trial ended prematurely?

Main objective of the trial

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

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

06 Jul 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 5

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Poland: 1

Country: Number of subjects enrolled

Spain: 12

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 31

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants were randomized at 33 sites globally. The sites were located in: Australia (3), Europe (18) and the United States (12).

Screening details

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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Stable Disease (SD) Cohort: Oral Azacitidine

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

CC-486

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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.

Progressive Disease (PD) Cohort: Oral Azacitidine

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

CC-486

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Stable Disease Cohort: Oral Azacitidine and Durvalumab

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

Other name

Imfinzi, MEDI4736

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

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

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

CC-486

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Progressive Disease Cohort: Oral Azacitidine and Durvalumab

Arm 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.

Arm type

Experimental

Investigational medicinal product name

Durvalumab

Investigational medicinal product code

Other name

Imfinzi, MEDI4736

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

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

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

CC-486

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	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
Started	32	22	6	5
Completed	3	1	1	0
Not completed	29	21	5	5
Adverse event, serious fatal	21	18	3	5
Consent withdrawn by subject	2	2	-	-
Adverse event, non-fatal	1	-	-	-
Site Closure by Sponsor	5	1	2	-

Baseline characteristics

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Reporting group title

Stable Disease (SD) Cohort: Oral Azacitidine

Reporting group description

Reporting group title

Progressive Disease (PD) Cohort: Oral Azacitidine

Reporting group description

Reporting group title

Stable Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

Reporting group title

Progressive Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

Reporting group values	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	Total
Number of subjects	32	22	6	5	65
Age categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	2	2	3	0	7
From 65-84 years	29	18	3	5	55
85 years and over	1	2	0	0	3
Age Continuous
Units: Years
arithmetic mean (standard deviation)	73.9 ( 7.62 )	75.1 ( 7.56 )	70.0 ( 7.21 )	72.4 ( 5.55 )	-
Sex: Female, Male
Units: Participants
Female	12	7	0	0	19
Male	20	15	6	5	46
Race/Ethnicity, Customized
Units: Subjects
White	28	18	6	5	57
Black	0	1	0	0	1
Asian	1	1	0	0	2
Native Hawaiian or Other Pacific Islander	0	1	0	0	1
American Indian or Alaska Native	0	0	0	0	0
Other	1	1	0	0	2
Not Collected or Reported	2	0	0	0	2
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	1	1	0	2	4
Not Hispanic or Latino	30	21	6	3	60
Unknown	1	0	0	0	1
Myelodysplastic Syndrome (MDS) World Health Organization Classification 2008
The World Health Organization (WHO) 2008 classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.
Units: Subjects
Refractory Anemia (RA) with Ringed Sideroblasts	1	0	0	0	1
Refractory Cytopenia with Multilineage Dysplasia	11	2	1	0	14
RA With Excess Blasts-1 (RAEB-1)	10	6	1	2	19
RA With Excess Blasts-2 (RAEB-2)	8	11	4	3	26
MDS Unclassified (MDS-U)	1	3	0	0	4
MDS Associated with Isolated del (5q)	0	0	0	0	0
Missing	1	0	0	0	1
International Prognostic Scoring System Risk Classification
The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis.
Units: Subjects
Low (0)	4	2	0	0	6
Intermediate 1 (0.5-1.0)	12	5	1	2	20
Intermediate (2) (1.0-2.0)	7	7	4	2	20
High (2) (≥ 2.5)	8	8	1	1	18
Unknown	1	0	0	0	1
French-American-British (FAB) Classification
FAB is a classification system for five (5) subtypes of myelodysplastic syndrome that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts or a monocytosis.
Units: Subjects
Refractory Anemia (RA)	6	2	0	0	8
Refractory Anemia with Ringed Sideroblasts (RARS)	6	1	1	0	8
Refractory Anemia with Excess Blasts (RAEB)	17	16	5	4	42
RAEB in Transformation	2	3	0	1	6
Chronic Myelomonocytic Leukemia (CMML)	0	0	0	0	0
Missing	1	0	0	0	1
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
ECOG performance status is used by doctors and researchers to assess how a subject's disease is progressing, assess how the disease affects the daily living activities of the subject and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity); 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, No self-care (Least Favorable Activity)
Units: Subjects
0 (Fully active)	5	6	3	2	16
1 (Restricted but Ambulatory)	22	13	3	3	41
2 (Ambulatory But Unable to Work)	5	3	0	0	8
3 (Limited Self-Care)	0	0	0	0	0
4 (Completely Disabled)	0	0	0	0	0
5 (Death)	0	0	0	0	0
Baseline Platelet Transfusion Status
Baseline Platelet transfusion dependence is defined as ≥ 2 transfusions (in units) during the 56 days prior to treatment. Platelet transfusion independence is defined as 0 transfusions (in units) during the 56 days prior to treatment.
Units: Subjects
Dependent	4	5	0	1	10
Independent	25	13	6	4	48
Other	3	4	0	0	7
Baseline Red Blood Cell (RBC) Transfusion Status
Baseline RBC Transfusion Dependence is defined as ≥ 4 transfusions (in units) during the 56 days prior to treatment. RBC transfusion independence is defined as 0 transfusions (in units) during the 56 days prior to treatment.
Units: Subjects
Dependent	8	7	0	2	17
Independent	8	6	3	2	19
Other	16	9	3	1	29
Average Red Blood Cell (RBC) Transfusion Requirement
Documentation of all red blood cell transfusions received by the participant within 8 weeks (56 days) prior to the first dose of study drug.
Units: units per 56 days
median (full range (min-max))	4.00 (0.00 to 10.0)	3.50 (0.0 to 7.0)	3.00 (0.0 to 7.0)	4.00 (0.0 to 15.0)	-

End points

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Reporting group title

Stable Disease (SD) Cohort: Oral Azacitidine

Reporting group description

Reporting group title

Progressive Disease (PD) Cohort: Oral Azacitidine

Reporting group description

Reporting group title

Stable Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

Reporting group title

Progressive Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

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

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End point title

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

End point 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)

End point type

Primary

End point 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

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical analysis was not planned as per study plan.

End point values	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
Number of subjects analysed	32	22	6	5
Units: Percentage of Participants
number (confidence interval 95%)	6.3 (0.8 to 20.8)	4.5 (0.1 to 22.8)	16.7 (0.4 to 64.1)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Overall Survival

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End point title

Kaplan-Meier Estimate of Overall Survival

End point 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.

End point type

Secondary

End point timeframe

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

End point values	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
Number of subjects analysed	32	22	6	5
Units: Months
median (confidence interval 95%)	17.00 (10.03 to 24.99)	6.28 (4.50 to 15.19)	14.70 (1.58 to 99999)	14.56 (9.73 to 99999)

No statistical analyses for this end point

Secondary: Kaplan Meier Estimate of Time to Onset of First and Best Response

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End point title

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

End point 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.

End point type

Secondary

End point timeframe

End point values	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
Number of subjects analysed	32	22	6	5
Units: Months
median (confidence interval 95%)
Onset of First Response	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
Onset of Best Response	3.68 (2.10 to 99999)	4.41 (1.68 to 99999)	3.29 (1.64 to 99999)	2.17 (1.64 to 99999)

No statistical analyses for this end point

Secondary: Kaplan Meier Estimate of Duration of First Response

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End point title

Kaplan Meier Estimate of Duration of First Response ^[2]

End point 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.

End point type

Secondary

End point timeframe

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned as per study plan.

End point values	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab
Number of subjects analysed	3	2	1
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Kaplan Meier Estimate of Duration of Best Response

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End point title

Kaplan Meier Estimate of Duration of Best Response

End point description

End point type

Secondary

End point timeframe

End point values	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
Number of subjects analysed	32	22	6	5
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

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End point title

Kaplan-Meier Estimate of Progression Free Survival (PFS)

End point description

Progression-free survival is defined as the time from first dose 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

End point type

Secondary

End point timeframe

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

End point values	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
Number of subjects analysed	32	22	6	5
Units: Months
median (confidence interval 95%)	14.86 (9.27 to 24.99)	6.28 (4.50 to 15.19)	14.70 (1.58 to 99999)	12.10 (2.17 to 99999)

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Onset to Achieve Stable Disease

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End point title

Kaplan-Meier Estimate of Onset to Achieve Stable Disease ^[3]

End point description

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

End point type

Secondary

End point timeframe

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned as per study plan.

End point values	Progressive Disease (PD) Cohort: Oral Azacitidine	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Number of subjects analysed	22	5
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Progressive Disease at Baseline who Achieved Stable Disease

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End point title

Percentage of Participants with Progressive Disease at Baseline who Achieved Stable Disease ^[4]

End point description

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

End point type

Secondary

End point timeframe

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned as per study plan.

End point values	Progressive Disease (PD) Cohort: Oral Azacitidine	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Number of subjects analysed	22	5
Units: Percentage of Participants
number (not applicable)	36.4	20.0

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Duration of Stable Disease

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End point title

Kaplan-Meier Estimate of Duration of Stable Disease ^[5]

End point 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.

End point type

Secondary

End point timeframe

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis was not planned as per study plan.

End point values	Stable Disease (SD) Cohort: Oral Azacitidine	Progressive Disease (PD) Cohort: Oral Azacitidine	Progressive Disease Cohort: Oral Azacitidine and Durvalumab
Number of subjects analysed	32	22	5
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants who Progressed to Acute Myelogenous Leukemia (AML)

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End point title

Percentage of Participants who Progressed to Acute Myelogenous Leukemia (AML)

End point 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.

End point type

Secondary

End point timeframe

From first dose and until death, loss to follow-up, withdrawal of consent for further data collection, or study closure (Up to 91 months)

End point values	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
Number of subjects analysed	32	22	6	5
Units: Percentage of Participants
number (not applicable)	31.3	18.2	33.3	60.0

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimate of Time to Progression to AML

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End point title

Kaplan-Meier Estimate of Time to Progression to AML

End point 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.

End point type

Secondary

End point timeframe

From first dose and until death, loss to follow-up, withdrawal of consent for further data collection, or study closure (Up to 91 months)

End point values	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
Number of subjects analysed	32	22	6	5
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	21.47 (1.68 to 99999)	6.21 (1.64 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Participants with Treatment Emergent Adverse Events (TEAEs)

End point 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.

End point type

Secondary

End point 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 study visit, whichever date is later (Up to 91 months)

End point values	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
Number of subjects analysed	32	22	6	5
Units: Participants
≥ 1 TEAE	32	22	6	5
≥ 1 TEAE Related to (R/T) Oral Azacitidine (AZA)	28	20	6	4
≥ 1 TEAE R/T Durvalumab (Durva)	0	0	5	4
≥ 1 TEAE R/T Oral AZA or Durva	28	20	6	4
≥ 1 Serious TEAE	25	15	4	5
≥ 1 Serious TEAE R/T Oral AZA	4	3	2	1
≥ 1 Serious TEAE R/T Durva	0	0	1	1
≥ 1 Serious TEAE R/T Oral AZA or Durva	4	3	2	1
≥ 1 NCI CTC Grade (GR) 3 or 4 TEAE	32	19	5	5
≥ 1 NCI CTC GR 3 or 4 TEAE R/T Oral AZA	18	10	4	3
≥ 1 NCI CTC GR 3 or 4 TEAE R/T Durva	0	0	2	2
≥ 1 NCI CTC GR 3 or 4 TEAE R/T AZA or Durva	18	10	4	3
≥ 1 TEAE Leading to Death	4	4	2	0
≥ 1 TEAE Leading to Death R/T Oral AZA	0	0	0	0
≥ 1 TEAE Leading to Death R/T Durva	0	0	0	0
≥ 1 TEAE Leading to Death R/T AZA or Durva	0	0	0	0
≥ 1 TEAE Leading to Dose Reduction of AZA	10	8	1	0
≥ 1 TEAE Leading to Reduction of Durva	0	0	0	0
≥ 1 TEAE Leading to Reduction of AZA or Durva	10	8	1	0
≥1 TEAE Leading to Interruption of AZA	21	13	3	4
≥1 TEAE Leading to Interruption of Durva	0	0	2	0
≥1 TEAE Leading to Interruption of AZA or Durva	21	13	3	4
≥ 1 TEAE Leading to Discontinuation (D/C) of AZA	15	8	4	4
≥ 1 TEAE Leading to D/C of Durva	0	0	3	3
≥ 1 TEAE Leading to D/C of AZA or Durva	15	8	4	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAE and Non-SAEs were collected from first dose, until 28 days after the last dose of CC-486 (90 days after the last dose of durvalumab) or the last study visit, whichever date is later. (Up to 91 months)

Adverse event reporting additional description

The number at Risk for All-Cause Mortality represents all enrolled participants. The number at risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents safety population that include all enrolled subjects who have received at least 1 dose of IP and had at least 1 post-dose safety assessment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Stable Disease (SD) Cohort: Oral Azacitidine

Reporting group description

Reporting group title

Stable Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

Reporting group title

Progressive Disease Cohort: Oral Azacitidine and Durvalumab

Reporting group description

Reporting group title

Progressive Disease (PD) Cohort: Oral Azacitidine

Reporting group description

Serious adverse events	Stable Disease (SD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease (PD) Cohort: Oral Azacitidine
Total subjects affected by serious adverse events
subjects affected / exposed	26 / 32 (81.25%)	4 / 6 (66.67%)	5 / 5 (100.00%)	15 / 22 (68.18%)
number of deaths (all causes)	22	3	5	18
number of deaths resulting from adverse events	4	2	0	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Glioma
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transformation to acute myeloid leukaemia
subjects affected / exposed	8 / 32 (25.00%)	1 / 6 (16.67%)	3 / 5 (60.00%)	3 / 22 (13.64%)
occurrences causally related to treatment / all	0 / 8	0 / 1	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sarcoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary oedema
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
White blood cell count increased
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dementia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 32 (6.25%)	2 / 6 (33.33%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperleukocytosis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Haematemesis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune hepatitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erythema
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyoderma gangrenosum
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fungaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis gangrenous
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Neutropenic sepsis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	9 / 32 (28.13%)	0 / 6 (0.00%)	2 / 5 (40.00%)	2 / 22 (9.09%)
occurrences causally related to treatment / all	1 / 10	0 / 0	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Serratia bacteraemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Tumour lysis syndrome
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Stable Disease (SD) Cohort: Oral Azacitidine	Stable Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease Cohort: Oral Azacitidine and Durvalumab	Progressive Disease (PD) Cohort: Oral Azacitidine
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 32 (100.00%)	6 / 6 (100.00%)	5 / 5 (100.00%)	22 / 22 (100.00%)
Vascular disorders
Haematoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	1	0	1	1
Hypertension
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Hypotension
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	3 / 5 (60.00%)	1 / 22 (4.55%)
occurrences all number	1	0	3	1
Superficial vein thrombosis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	7 / 32 (21.88%)	1 / 6 (16.67%)	1 / 5 (20.00%)	3 / 22 (13.64%)
occurrences all number	10	3	2	5
Generalised oedema
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Fatigue
subjects affected / exposed	10 / 32 (31.25%)	2 / 6 (33.33%)	4 / 5 (80.00%)	6 / 22 (27.27%)
occurrences all number	33	3	7	6
Chills
subjects affected / exposed	1 / 32 (3.13%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	1	1	0
Catheter site erythema
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Asthenia
subjects affected / exposed	9 / 32 (28.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	4 / 22 (18.18%)
occurrences all number	9	0	0	5
Oedema peripheral
subjects affected / exposed	6 / 32 (18.75%)	1 / 6 (16.67%)	3 / 5 (60.00%)	2 / 22 (9.09%)
occurrences all number	6	1	4	2
Immune system disorders
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Reproductive system and breast disorders
Penile pain
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Oedema genital
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	2 / 5 (40.00%)	1 / 22 (4.55%)
occurrences all number	4	0	2	1
Dyspnoea exertional
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	4	0	0	1
Dyspnoea
subjects affected / exposed	9 / 32 (28.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	4 / 22 (18.18%)
occurrences all number	13	0	0	4
Cough
subjects affected / exposed	7 / 32 (21.88%)	0 / 6 (0.00%)	1 / 5 (20.00%)	4 / 22 (18.18%)
occurrences all number	7	0	2	4
Hypoxia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Nasal congestion
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	1	0	0	2
Oropharyngeal pain
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	4	0	0	2
Pleural effusion
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Productive cough
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	3	0	0	2
Pulmonary hypertension
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Psychiatric disorders
Irritability
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Insomnia
subjects affected / exposed	6 / 32 (18.75%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	7	0	1	2
Depression
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	0	0	1	2
Delirium
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	1 / 5 (20.00%)	4 / 22 (18.18%)
occurrences all number	2	0	5	4
Aspartate aminotransferase increased
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	2	0	9	1
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Blood creatinine increased
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	5	0	0	1
Cardiac murmur
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0
Platelet count decreased
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	2	0	0
Serum ferritin increased
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Urine output decreased
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Weight decreased
subjects affected / exposed	10 / 32 (31.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	6 / 22 (27.27%)
occurrences all number	11	0	0	6
White blood cell count increased
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	5 / 32 (15.63%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	7	0	0	0
Skin wound
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Spinal compression fracture
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Transfusion reaction
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	2	0	1	3
Contusion
subjects affected / exposed	5 / 32 (15.63%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	14	0	0	2
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0
Atrial fibrillation
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences all number	1	0	2	0
Tricuspid valve disease
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Tachycardia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Sinus tachycardia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences all number	0	0	2	0
Sinus bradycardia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Nervous system disorders
Somnolence
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Sciatica
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Headache
subjects affected / exposed	4 / 32 (12.50%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	12	4	0	1
Dysgeusia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Dizziness
subjects affected / exposed	6 / 32 (18.75%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	14	0	0	2
Lethargy
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	0	1
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	4	0	1	0
Neutropenia
subjects affected / exposed	12 / 32 (37.50%)	1 / 6 (16.67%)	2 / 5 (40.00%)	6 / 22 (27.27%)
occurrences all number	42	1	4	18
Anaemia
subjects affected / exposed	12 / 32 (37.50%)	1 / 6 (16.67%)	3 / 5 (60.00%)	10 / 22 (45.45%)
occurrences all number	40	1	18	28
Splenomegaly
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Thrombocytopenia
subjects affected / exposed	8 / 32 (25.00%)	1 / 6 (16.67%)	4 / 5 (80.00%)	6 / 22 (27.27%)
occurrences all number	11	2	11	6
Ear and labyrinth disorders
Vertigo positional
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Hypoacusis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Ear pain
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Eye disorders
Conjunctival haemorrhage
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Eye haemorrhage
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	21 / 32 (65.63%)	4 / 6 (66.67%)	2 / 5 (40.00%)	11 / 22 (50.00%)
occurrences all number	41	4	2	26
Constipation
subjects affected / exposed	13 / 32 (40.63%)	1 / 6 (16.67%)	2 / 5 (40.00%)	9 / 22 (40.91%)
occurrences all number	25	1	3	12
Dry mouth
subjects affected / exposed	1 / 32 (3.13%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	1	1	0
Abdominal pain upper
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	12	0	0	0
Abdominal pain
subjects affected / exposed	3 / 32 (9.38%)	2 / 6 (33.33%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	6	2	2	2
Abdominal distension
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	4	0	0	1
Anal erythema
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0
Gingival bleeding
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	4	0	1	1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	2
Flatulence
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	3	0	0	1
Dysphagia
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	2	0	0
Dyspepsia
subjects affected / exposed	1 / 32 (3.13%)	2 / 6 (33.33%)	1 / 5 (20.00%)	3 / 22 (13.64%)
occurrences all number	1	3	1	3
Duodenogastric reflux
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0
Haemorrhoids
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Stomatitis
subjects affected / exposed	4 / 32 (12.50%)	1 / 6 (16.67%)	1 / 5 (20.00%)	3 / 22 (13.64%)
occurrences all number	4	1	1	3
Periodontal disease
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Oral mucosa haematoma
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Nausea
subjects affected / exposed	24 / 32 (75.00%)	2 / 6 (33.33%)	2 / 5 (40.00%)	12 / 22 (54.55%)
occurrences all number	34	6	3	17
Mouth haemorrhage
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences all number	1	0	2	0
Vomiting
subjects affected / exposed	18 / 32 (56.25%)	2 / 6 (33.33%)	3 / 5 (60.00%)	11 / 22 (50.00%)
occurrences all number	25	3	5	25
Skin and subcutaneous tissue disorders
Erythema multiforme
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Night sweats
subjects affected / exposed	1 / 32 (3.13%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	1	0	0
Petechiae
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	10	0	0	0
Pruritus
subjects affected / exposed	5 / 32 (15.63%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	6	0	0	1
Rash
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	0	0	0
Decubitus ulcer
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1
Dermatitis bullous
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Urticaria
subjects affected / exposed	1 / 32 (3.13%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	1	0	0
Rash maculo-papular
subjects affected / exposed	3 / 32 (9.38%)	1 / 6 (16.67%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	3	1	1	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	1	0	2	2
Pollakiuria
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	0	1
Dysuria
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	0	0	0
Renal cyst
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	2	0	1	0
Urinary tract obstruction
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Urinary retention
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	0	0	3
Urinary incontinence
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	1	0	1	0
Renal disorder
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	4 / 32 (12.50%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	7	0	2	1
Muscle spasms
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	1	0	0
Joint effusion
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	0	0	1
Back pain
subjects affected / exposed	7 / 32 (21.88%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	9	0	1	1
Arthralgia
subjects affected / exposed	5 / 32 (15.63%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 22 (13.64%)
occurrences all number	7	0	0	3
Polyarthritis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Myalgia
subjects affected / exposed	3 / 32 (9.38%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	5	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	2	1	0	0
Folliculitis
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 22 (13.64%)
occurrences all number	0	0	0	3
Diverticulitis
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	3	0	0	0
Cellulitis
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	0	0	2
Urinary tract infection
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	6	0	0	2
Upper respiratory tract infection
subjects affected / exposed	6 / 32 (18.75%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	13	1	0	3
Staphylococcal infection
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Rash pustular
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	1	0
Pneumonia
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	2 / 5 (40.00%)	2 / 22 (9.09%)
occurrences all number	3	0	3	2
Oral herpes
subjects affected / exposed	5 / 32 (15.63%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	5	0	0	1
Oral candidiasis
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	15 / 32 (46.88%)	1 / 6 (16.67%)	2 / 5 (40.00%)	8 / 22 (36.36%)
occurrences all number	23	1	2	8
Dehydration
subjects affected / exposed	2 / 32 (6.25%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 22 (4.55%)
occurrences all number	2	1	0	1
Gout
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	0	0	0
Hyperkalaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 22 (13.64%)
occurrences all number	2	0	0	5
Hyperglycaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	9	0	2	0
Hypophosphataemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	3
Hypomagnesaemia
subjects affected / exposed	3 / 32 (9.38%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	3	0	3	2
Hypokalaemia
subjects affected / exposed	4 / 32 (12.50%)	0 / 6 (0.00%)	2 / 5 (40.00%)	0 / 22 (0.00%)
occurrences all number	4	0	8	0
Hypocalcaemia
subjects affected / exposed	2 / 32 (6.25%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 22 (9.09%)
occurrences all number	2	0	0	2
Hypoalbuminaemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 22 (0.00%)
occurrences all number	0	0	3	0
Hyperuricaemia
subjects affected / exposed	0 / 32 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	2 / 22 (9.09%)
occurrences all number	0	1	1	2
Hyperphosphataemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 22 (4.55%)
occurrences all number	0	0	1	1

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Were there any global substantial amendments to the protocol? Yes

08 Sep 2015

An additional investigational product (IP), anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736) in combination with CC-486 (combination therapy), was to be evaluated in this study in addition to the evaluation of CC-486 as monotheraphy.

27 Mar 2017

Updated objectives, futility analysis, enrollment period, safety profile, and dosing for clarity and extended trial duration.

28 Dec 2017

Protocol text was updated to allow the dose escalation of CC-486 after 2 well tolerated cycles (instead of 4 cycles). The safety assessment observed in the Phase 1 safety run-in portion of the trial was based on 2 dosing cycles and most adverse events occurred early in these cycles.

17 Jun 2019

A description of the Extension Phase was presented in Appendix J and mentioned throughout the protocol. The overall duration of the study was extended during the Extension Phase

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Kaplan-Meier Estimate of Overall Survival

Secondary: Kaplan-Meier Estimate of Overall Survival

Secondary: Kaplan Meier Estimate of Time to Onset of First and Best Response

Secondary: Kaplan Meier Estimate of Time to Onset of First and Best Response

Secondary: Kaplan Meier Estimate of Duration of First Response

Secondary: Kaplan Meier Estimate of Duration of First Response

Secondary: Kaplan Meier Estimate of Duration of Best Response

Secondary: Kaplan Meier Estimate of Duration of Best Response

Secondary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

Secondary: Kaplan-Meier Estimate of Progression Free Survival (PFS)

Secondary: Kaplan-Meier Estimate of Onset to Achieve Stable Disease

Secondary: Kaplan-Meier Estimate of Onset to Achieve Stable Disease

Secondary: Percentage of Participants with Progressive Disease at Baseline who Achieved Stable Disease

Secondary: Percentage of Participants with Progressive Disease at Baseline who Achieved Stable Disease

Secondary: Kaplan-Meier Estimate of Duration of Stable Disease

Secondary: Kaplan-Meier Estimate of Duration of Stable Disease

Secondary: Percentage of Participants who Progressed to Acute Myelogenous Leukemia (AML)

Secondary: Percentage of Participants who Progressed to Acute Myelogenous Leukemia (AML)

Secondary: Kaplan-Meier Estimate of Time to Progression to AML

Secondary: Kaplan-Meier Estimate of Time to Progression to AML

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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