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Clinical Trial Results:
A Phase 2, Multicenter, Open-label Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety and Activity of Azacitidine and to Compare Azacitidine to Historical Controls in Pediatric Subjects With Newly Diagnosed Advanced Myelodysplastic Syndrome or Juvenile Myelomonocytic Leukemia Before Hematopoietic Stem Cell Transplantation

Summary
EudraCT number	2014-002388-13
Trial protocol	DE ES GB IE AT CZ BE IT SE DK NL FR
Global end of trial date	23 May 2019

Results information
Results version number	v1(current)
This version publication date	18 Dec 2019
First version publication date	18 Dec 2019
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

AZA-JMML-001

ISRCTN number

US NCT number

NCT02447666

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com

Scientific contact

Bouchra Benettaib, MD, Celgene Corporation, 01 908 673 9194, BBenettaib@celgene.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?

Yes

Analysis stage

Final

Date of interim/final analysis

23 May 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 May 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective was to assess the treatment effect on response rate [myelodysplastic syndrome (MDS): either complete remission [CR], partial remission [PR], or marrow CR; juvenile myelomonocytic leukemia (JMML): either clinical complete remission [cCR] or clinical partial remission [cPR]); at Cycle 3 Day 28 and to compare against standard therapy using a matched-pairs analysis of historical data.

Protection of trial subjects

Informed Consent, Patient Confidentiality, Archiving of Essential Documents

Background therapy

Evidence for comparator

Actual start date of recruitment

02 Sep 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 3

Country: Number of subjects enrolled

Denmark: 1

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Netherlands: 1

Country: Number of subjects enrolled

Spain: 2

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Switzerland: 1

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

Subjects were enrolled at 18 sites in the Czech Republic, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, Sweden and Switzerland.

Screening details

The study consisted of 2 cohorts: subjects aged 1 month to less than 18 years of age with newly diagnosed MDS or with newly diagnosed JMML prior to hematopoietic stem cell transplantation (HSCT) were enrolled in Stage 1 of the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MDS: Azacitdine

Arm description

Subjects with myelodysplastic syndrome received azacitidine 75 mg/m^2, either by intravenous (IV) infusion or by subcutaneous (SC) injection, on Days 1 to 7 of each 28-day treatment cycle for a minimum of 3 cycles and a maximum of 6 cycles, unless disease progression occurred.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Vidaza

Pharmaceutical forms

Solution for infusion, Solution for injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Azacitidine 75 mg/m^2, either by IV infusion or by SC injection, on Days 1 to 7 of each 28-day treatment cycle

JMML: Azacitidine

Arm description

Subjects with JMML received azacitidine 75 mg/m^2, either by IV infusion or by SC injection on Days 1 to 7 of each 28-day treatment cycle for a minimum of 3 cycles and a maximum of 6 cycles, unless disease progression occurred.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Vidaza

Pharmaceutical forms

Solution for infusion, Solution for injection

Routes of administration

Intravenous use, Subcutaneous use

Dosage and administration details

Azacitidine 75 mg/m^2, either by IV infusion or by SC injection, on Days 1 to 7 of each 28-day treatment cycle

Number of subjects in period 1	MDS: Azacitdine	JMML: Azacitidine
Started	10	18
Completed	7	15
Not completed	3	3
Physician decision	2	-
Adverse event, non-fatal	1	1
Progressive Disease	-	2

Baseline characteristics

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Reporting group title

MDS: Azacitdine

Reporting group description

Reporting group title

JMML: Azacitidine

Reporting group description

Reporting group values	MDS: Azacitdine	JMML: Azacitidine	Total
Number of subjects	10	18	28
Age Categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	1	10	11
Children (2-11 years)	2	8	10
Adolescents (12-17 years)	7	0	7
Adults (18-64 years)	0	0	0
From 65-84 years	0	0	0
85 years and over	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	11.16 ± 4.862	2.38 ± 1.685	-
Gender Categorical
Units: Subjects
Female	4	7	11
Male	6	11	17
Ethnicity
Units: Subjects
Hispanic or Latino	0	1	1
Not Hispanic or Latino	10	16	26
Not Reported	0	1	1
Unknown	0	0	0
Primary Race
Units: Subjects
American Indian	0	0	0
Asian	0	0	0
Black or African American	0	0	0
Native Hawiian or Other Pacific Islander	0	0	0
White	10	16	26
Not Collected or Reported	0	1	1
Other	0	1	1
Newly Diagnosed Advanced Myelodysplastic Syndrome Diagnosis
Myelodysplastic syndrome in children can be divided into primary and secondary. If no cause can be identified, it is called primary MDS. Myelodysplastic syndrome after prior chemotherapy or radiation therapy, after prior acquired aplastic anemia, or in inherited bone marrow (BM) failure disorders is classified as secondary MDS.
Units: Subjects
Primary	10	0	10
Secondary	0	0	0
Other	0	18	18
Newly Diagnosed Advanced Myelodysplastic Syndrome Classification
Newly diagnosed advanced primary or secondary MDS, with one of the following: - Refractory anemia with excess blasts (RAEB): 2% to 19% blasts in peripheral blood (PB) or 5% to 19% blasts in bone marrow (BM). - Refractory anemia with excess blasts in transformation (RAEB-t): 20% to 29% of blasts in PB or BM. - Secondary MDS presenting as Chronic myelomonocytic leukemia (CMML) without increase in blasts but with chromosomal abnormality
Units: Subjects
Refractory Anemia with Excess Blasts (RAEB)	6	0	6
RAEB in Transformation (RAEB-t)	4	0	4
2ndary MDS Presenting as CMML	0	0	0
Other	0	18	18
Juvenile Myelomonocytic Leukemia Diagnostics
Newly diagnosed JMML, with one of the following: - somatic mutation in PTPN11-gene (PTPN11) - somatic mutation in (KRAS-gene) KRAS - somatic mutation in (NRAS - gene) NRAS and (fetal hemoglobin) HbF % > 5x normal value for age - clinical diagnosis of neurofibromatosis Type 1.
Units: Subjects
Somatic Mutations in PTPN 11	0	13	13
Somatic Mutation in KRAS	0	1	1
Somatic Mutation in NRAS and HbF% >5 x's Normal	0	3	3
Clinical Diagnosis of Neurofibromatosis Type 1	0	1	1
Other	10	0	10
Methylation Class
Unsupervised cluster analyses of methylation profiles in JMML samples, using the 1,000 most variables JMML differentially methylated probe (DMPs) mapping to CpG islands to identify high, intermediate or low methylation classes. JMML methylation class clusters into 3 subgroups ie., high, intermediate and low.
Units: Subjects
High	0	11	11
Intermediate	0	5	5
Low	0	2	2
MDS: Not Done	10	0	10
Time From Initial Diagnosis
Units: days
median (full range (min-max))	7.5 (1.0 to 25.0)	24.5 (1.0 to 73.0)	-

End points

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Reporting group title

MDS: Azacitdine

Reporting group description

Reporting group title

JMML: Azacitidine

Reporting group description

Primary: MDS Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

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End point title

MDS Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review ^[1] ^[2]

End point description

The response rate was defined as the percentage of subjects with a confirmed complete remission (CR), partial remission (PR) or marrow complete remission (mCR), according to modified International Working Group (IWG) response criteria, adapted to pediatric reference values at 3 months. Response must have been sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3 Day 28. A CR = ≤ 5% myeloblasts in bone marrow (BM), and peripheral blood (PB) Hemoglobin (hgb) ≥ 9 g/dL (1-12 months), ≥ 10 g/dL (13 months-11years, ≥11 g/dL (≥12 months) Platelets ≥ 100 × 10^⁹/L Neutrophils ≥ 1.0 × 10^⁹/L Blasts 0% PR= CR criteria if abnormal before treatment except BM blasts decreased by ≥ 50% over pretreatment but still > 5%; Cellularity and morphology not relevant for PB; mCR: BM ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment. Intent to treat population = all subjects enrolled regardless of whether or not they received any dose of the study drug.

End point type

Primary

End point timeframe

Response was assessed at Cycle 3, Day 28; up to the data cut-off date of 13 March 2019; median treatment duration was 12 weeks (range: 5.0 to 12.7 weeks).

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: No statistical analysis was performed.
[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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10
Units: Percentage of Subjects
number (confidence interval 95%)	0.0 (0.0 to 30.8)

No statistical analyses for this end point

Primary: JMML Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

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End point title

JMML Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review ^[3] ^[4]

End point description

Response = the percentage of subjects with a sustained clinical CR (cCR) or cPR according to the International JMML response criteria at 3 months. Response had to be sustained for at least 4 weeks either in the 4-week period preceding or succeeding Cycle 3 Day 28. A cCR = WBC: ≥ 3.0 – 15.0 x10^⁹/L Myeloid, erythroid precursors and blasts in PB: 0-1% Platelet count ≥ 100 x10^⁹/L BM contains <5% blast cells, no splenomegaly by sonography, no extramedullary leukemic infiltration in an organ cPR = WBC: decreased by ≥ 50% over pretreatment but still >15 x 10^⁹/L Myeloid, erythroid precursors and blasts in PB decreased by ≥ 50% over pretreatment but yet ≥ 2% Platelet count = ≥ 20 × 10^9/L platelets, absolute increase of ≥ 30 × 10^9/L; those with < 20 × 10^9/L platelets: increase by ≥ 100% and > 20 × 10^9/L Blast cells decreased by ≥ 50% over pretreatment but ≥ 5.0% Splenic clinical evaluation and ≥ 25% decrease by length No extramedullary leukemic infiltration. ITT Population

End point type

Primary

End point timeframe

Response was assessed at Cycle 3, Day 28; up to the data cut-off date of 13 March 2019; median treatment duration was 12.29 weeks (range: 4.0 to 30.6 weeks).

Notes
[3] - 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: No statistical analysis was performed.
[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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18
Units: Percentage
number (confidence interval 95%)	50.0 (26.0 to 74.0)

No statistical analyses for this end point

Secondary: MDS Cohort: Number of Subjects who Achieved a Cytogenetic Response at Cycle 3 Day 28 Based on Central Review

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End point title

MDS Cohort: Number of Subjects who Achieved a Cytogenetic Response at Cycle 3 Day 28 Based on Central Review ^[5]

End point description

The cytogenetic response was defined as the number of subjects with complete disappearance of the chromosomal abnormality without appearance of new ones according to the modified IWG 2006 response criteria for MDS. Subjects with a response observed after hematopoietic stem cell transplantation (HSCT) were censored. Responses occurring after start of a new anticancer therapy were censored. ITT population evaluable for cytogenetic response.

End point type

Secondary

End point timeframe

Response was assessed at Cycle 3, Day 28; up to the data cut-off date of 13 March 2019; for MDS subjects, median treatment duration was 12 weeks (range: 5.0 to 12.7 weeks).

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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10
Units: Subjects
number (not applicable)
Definite Cytogenetic Response	1
No Cytogenetic Response	6
Missing Cytogenetic Response	3

No statistical analyses for this end point

Secondary: JMML Cohorts: Number of Subjects who Achieved a Genetic and Molecular Response at Cycle 3 Day 28 Based on Central Review

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End point title

JMML Cohorts: Number of Subjects who Achieved a Genetic and Molecular Response at Cycle 3 Day 28 Based on Central Review ^[6]

End point description

The cytogenetic response is defined as the number of subjects with complete disappearance of the chromosomal abnormality without appearance of new ones. A molecular response rate was defined as the number of subjects with absence of somatic mutations related to JMML. ITT population evaluable for cytogenetic and molecular response.

End point type

Secondary

End point timeframe

Response was assessed at Cycle 3, Day 28; up to data cut-off date of 13 March 2019; median treatment duration was 12.29 weeks (range: 4.0 to 30.6 weeks).

Notes
[6] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18
Units: Subjects
number (not applicable)
Genetic Response	2
No Genetic Response	14
Missing Genetic Response	2
Molecular Response	2

No statistical analyses for this end point

Secondary: MDS Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

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End point title

MDS Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review ^[7]

End point description

Duration of response (DoR) consisted of only the subjects who achieved a response (CR, PR or marrow CR) and was defined as the time from first observed response until either disease progression or any cause of death. Only subjects with a response observed before HSCT (or a new anticancer therapy) were included in the analysis. If no relapse, PD, or death was observed, the duration of response was censored at the last response assessment date that the subject was known to be progression-free.

End point type

Secondary

End point timeframe

Time from first observed response until disease progression until any cause of death; up to data cut-off date of 13 March 2019; median treatment duration was 12 weeks (range: 5.0 to 12.7 weeks).

Notes
[7] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	1 ^[8]
Units: Months
median (confidence interval 95%)	99999 (-99999 to 99999)

Notes
[8] - 99999 = not estimable due to a HSCT or another treatment the subject received.

No statistical analyses for this end point

Secondary: JMML Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

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End point title

JMML Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review ^[9]

End point description

Duration of response consisted of only the subjects who achieved a response and was defined as the time from the first overall response (clinical CR, cPR), whichever occurred first until either disease progression or any cause of death. ITT Population. Only subjects with a response observed before HSCT (or a new anticancer therapy) were included in the analysis. If no relapse, progressive disease (PD), or death was observed, the duration of response was censored at the last response assessment date that the subject was known to be progression-free.

End point type

Secondary

End point timeframe

Time from first observed response until disease progression until any cause of death; up to data cut-off date of 13 March 2019; median treatment duration was 12.29 weeks (range: 4.0 to 30.6 weeks).

Notes
[9] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18 ^[10]
Units: Days
median (confidence interval 95%)	99999 (-99999 to 99999)

Notes
[10] - 99999 = Not estimable due a HSCT or another treatment the subject received.

No statistical analyses for this end point

Secondary: MDS Cohort: Time to Response Based on Central Review

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End point title

MDS Cohort: Time to Response Based on Central Review ^[11]

End point description

Time to response (TTR) was defined as the time from first study dose day until a response (CR, PR or marrow CR for MDS whichever occurred first). ITT population. Only subjects with a response observed before HSCT (or a new anticancer therapy) were included in the analysis with the median TTR across the subjects presented. Responses that occurred after start of a new anticancer therapy were not considered.

End point type

Secondary

End point timeframe

Response was assessed following every treatment cycle until treatment discontinuation; up to data cut-off date of 13 March 2019; median treatment duration was 12 weeks (range: 5.0 to 12.7 weeks).

Notes
[11] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10 ^[12]
Units: Months
median (confidence interval 95%)	2.76 (-99999 to 99999)

Notes
[12] - 99999 = Not estimable due to the low number of responders

No statistical analyses for this end point

Secondary: JMML Cohort: Time to Response Based on Central Review

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End point title

JMML Cohort: Time to Response Based on Central Review ^[13]

End point description

Time to response was defined as the time from first study dose day until a response (cCR, cPR whichever occurred first). ITT population. Only subjects with a response observed before HSCT (or before a new anticancer therapy) were included in the analysis with the median TTR across the subjects presented. Responses that occurred after start of a new anticancer therapy were not considered.

End point type

Secondary

End point timeframe

Response was assessed following every treatment cycle until treatment discontinuation; up to data cut-off date of 13 March 2019; median treatment duration was 12.29 weeks (range: 4.0 to 30.6 weeks).

Notes
[13] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18
Units: Days
median (confidence interval 95%)	1.20 (0.95 to 1.87)

No statistical analyses for this end point

Secondary: MDS Cohort: Kaplan Meier Estimate of Time to Progression

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End point title

MDS Cohort: Kaplan Meier Estimate of Time to Progression ^[14]

End point description

Time to progression (TTP) was defined as the time from first study dose day until either disease progression or death due to progression. For subjects who were alive at the time of the analysis without an observed disease progression: • Subjects without an anticancer therapy and without HSCT were censored at the time of last date known alive • Subjects with HSCT were censored at the earliest date between HSCT and last date known alive. • Subjects who started an anticancer therapy but without HSCT were censored at the time of the last disease assessment before start of the anticancer therapy.

End point type

Secondary

End point timeframe

Time from first study dose day to either disease progression or death; up to the data cut-off date of 13 March 2019; median treatment duration was 12 weeks (range: 5.0 to 12.7 weeks).

Notes
[14] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10
Units: Months
median (confidence interval 95%)	0.97 (0.95 to 2.04)

No statistical analyses for this end point

Secondary: JMML Cohort: Kaplan Meier Estimate of Time to Progression

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End point title

JMML Cohort: Kaplan Meier Estimate of Time to Progression ^[15]

End point description

Time to progression was defined as the time from first study dose day until either disease progression or death due to progression. For subjects who were alive at the time of the analysis without an observed disease progression: • Subjects without an anticancer therapy and without HSCT were censored at the time of last date known alive • Subjects with HSCT were censored at the earliest date between HSCT and last date known alive. • Subjects who started an anticancer therapy but without HSCT were censored at the time of the last disease assessment before start of the anticancer therapy.

End point type

Secondary

End point timeframe

Time from first study dose day to either disease progression or death; up to data cut-off date of 13 March 2019; median treatment duration was 12.29 weeks (range: 4.0 to 30.6 weeks).

Notes
[15] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18 ^[16]
Units: Months
median (confidence interval 95%)	99999 (0.95 to 99999)

Notes
[16] - 99999 = Not estimable due to fewer than half of the subjects having disease progression.

No statistical analyses for this end point

Secondary: MDS Cohort: Kaplan Meier Estimate of Leukemia-Free Survival (LFS)

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End point title

MDS Cohort: Kaplan Meier Estimate of Leukemia-Free Survival (LFS) ^[17]

End point description

Leukemia-free survival was defined as the time from HSCT date until leukemia progression or death for subjects receiving a HSCT only. Subjects alive and leukemia-free at the time of the analysis were censored at the time of their last disease assessment. Subjects were also censored at the time of starting a new anticancer therapy if having not previously had a leukemia progression. ITT population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of study drug.

End point type

Secondary

End point timeframe

LFS was assessed up to data cut-off date of 24 May 2019; the median LFS follow up time was 22.47 months

Notes
[17] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10 ^[18]
Units: Months
median (confidence interval 95%)	99999 (13.60 to 99999)

Notes
[18] - 99999 = Not Estimable due to over 50% of subjects being censored

No statistical analyses for this end point

Secondary: JMML Cohort: Kaplan Meier Estimate of Leukemia-Free Survival

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End point title

JMML Cohort: Kaplan Meier Estimate of Leukemia-Free Survival ^[19]

End point description

End point type

Secondary

End point timeframe

LFS was assessed up to data cut-off date of 24 May 2019; the median LFS follow up time was 20.99 months

Notes
[19] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	17 ^[20]
Units: Months
median (confidence interval 95%)	99999 (-99999 to 99999)

Notes
[20] - 99999- median was not estimable due to over 50% of subjects being censored.

No statistical analyses for this end point

Secondary: MDS Cohort: Kaplan Meier Estimate of Overall Survival

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End point title

MDS Cohort: Kaplan Meier Estimate of Overall Survival ^[21]

End point description

Overall survival was defined as the time from first study dose day until death from any cause. Subjects alive at the time of analysis were censored at the time they were last known to be alive. ITT population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of the study drug.

End point type

Secondary

End point timeframe

From date of the first dose of study drug until death; up to the data-cut off date of 24 May 2019; median follow-up time was 25.72 months

Notes
[21] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10 ^[22]
Units: Months
median (confidence interval 95%)	99999 (18.37 to 99999)

Notes
[22] - 99999 = not estimable due to the majority of subjects being censored.

No statistical analyses for this end point

Secondary: JMML Cohort: Kaplan Meier Estimate of Overall Survival

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End point title

JMML Cohort: Kaplan Meier Estimate of Overall Survival ^[23]

End point description

Overall Survival (OS) was defined as the time from first study dose day until death from any cause. Subjects alive at the time of analysis were censored at the time they were last known to be alive. ITT population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of the study drug.

End point type

Secondary

End point timeframe

From date of the first dose of study drug until death; up to the data cut-off date of 24 May 2019; median follow-up time was 25.43 months

Notes
[23] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18 ^[24]
Units: Months
median (confidence interval 95%)	99999 (-99999 to 99999)

Notes
[24] - 99999 = median not estimable due to the majority of subjects alive at the time of the analysis.

No statistical analyses for this end point

Secondary: MDS Cohort: Percentage of Subjects Who Received a Hematopoietic Stem Cell Transplant (HSCT)

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End point title

MDS Cohort: Percentage of Subjects Who Received a Hematopoietic Stem Cell Transplant (HSCT) ^[25]

End point description

The rate of HSCT was defined as the percentage of subjects who received study dose and underwent a HSCT of the subjects in the ITT Population. ITT Population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of the study drug.

End point type

Secondary

End point timeframe

From the date of first dose of study drug to the end of the follow-up period; up to the data-cut off date of 13 March 2019

Notes
[25] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10
Units: Percentage
number (confidence interval 95%)	100.0 (69.2 to 100.0)

No statistical analyses for this end point

Secondary: JMML Cohort: Percentage of Subjects Who Received a HSCT

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End point title

JMML Cohort: Percentage of Subjects Who Received a HSCT ^[26]

End point description

The rate of HSCT was defined as percentage of subjects who received study drug and received a HSCT during the conduct of this study in the ITT population. ITT Population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of the study drug.

End point type

Secondary

End point timeframe

From the date of the first dose of study drug to the date of the HSCT; up to the data cut-off date of 13 March 2019.

Notes
[26] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18
Units: Percentage of Subjects
number (confidence interval 95%)	94.4 (72.7 to 99.9)

No statistical analyses for this end point

Secondary: MDS Cohort: Time to First Hematopoietic Stem Cell Transplant

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End point title

MDS Cohort: Time to First Hematopoietic Stem Cell Transplant ^[27]

End point description

Time to HSCT was defined as the time from first study dose day until HSCT date. Subjects not receiving a HSCT were censored at the time of the analysis. ITT Population was defined as all subjects enrolled into the study regardless of whether or not they received any dose of the study drug.

End point type

Secondary

End point timeframe

Date of first dose of study drug to the date the subjects received the HSCT; up to the data cut-off date of 13 March 2019

Notes
[27] - 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: No statistical analysis was performed.

End point values	MDS: Azacitdine
Number of subjects analysed	10
Units: Months
median (confidence interval 95%)	3.76 (2.79 to 4.73)

No statistical analyses for this end point

Secondary: JMML Cohort: Time to First Hematopoietic Stem Cell Transplant

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End point title

JMML Cohort: Time to First Hematopoietic Stem Cell Transplant ^[28]

End point description

End point type

Secondary

End point timeframe

Date of first dose of study drug to the date the subject received a HSCT; up to the data cut-off date of 13 March 2019

Notes
[28] - 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: No statistical analysis was performed.

End point values	JMML: Azacitidine
Number of subjects analysed	18
Units: Months
median (confidence interval 95%)	4.63 (3.91 to 6.77)

No statistical analyses for this end point

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

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End point title

Number of Participants with Treatment Emergent Adverse Events (TEAE)

End point description

TEAEs are adverse events that started or worsened between the date of first study drug dose and up to 28 days after the date of last dose. TEAEs were recorded by the Investigator from the day of the first dose of IP until 28 days after the last dose of azacitidine and those SAEs made known to the Investigator at any time thereafter that are suspected of being related to azacitidine. The severity of AEs were graded 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (version 4.0) and the severity was assessed by the investigator as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4) or death (grade 5). 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

End point type

Secondary

End point timeframe

From date of first dose of study drug up to 28 days after the last dose of azacitidine and for those SAEs made known to the investigator at any time during the study. Median treatment duration for MDS subjects = 12 weeks and 12.29 weeks for JMML subjects.

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: Subjects
≥ 1 TEAE	10	18
≥1 Grade (GR) 3-4 TEAE	7	10
≥ 1 TEAE Related to Azacitadine (AZA)	7	10
≥ 1 GR 3-4 TEAE Related to AZA	3	6
≥ 1 Serious TEAE	4	12
≥1 Serious TEAE Related to AZA	2	3
≥ 1 TEAE Leading to Dose Reduction of AZA	0	0
≥1 Serious TEAE leading to Dose Reduction of AZA	0	0
≥ 1 TEAE Leading to Dose Interruption of AZA	0	0
≥1 Serious TEAE leading to Dose Interrupt of AZA	0	0
≥ 1 TEAE Leading to Discontinuation of AZA	1	2
≥1 Serious TEAE leading to Discontinuation of AZA	1	2
≥ At Least 1 TEAE Leading to Death	0	0

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration (Cmax) of Azacitidine

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End point title

Maximum Plasma Concentration (Cmax) of Azacitidine

End point description

Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time The pharmacokinetic (PK) evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

Subjects ≤20 kg, Day 7 PK obtained post-dose: 5 min (IV treated), 15 min (SC treated), 30 min and 1, 4, 6, and 8 hours; subjects >20 kg, on Day 7: 1 hour pre-dose and post-dose = 5 min (IV treated), 15 min (SC treated), 30 min and 1, 2, 4, 6, and 8 hours.

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: ng/mL
geometric mean (geometric coefficient of variation)	1797.5 ± 133.6	1066.3 ± 215.3

No statistical analyses for this end point

Secondary: Time to Maximum Plasma Concentration (Tmax) of Azacitidine

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End point title

Time to Maximum Plasma Concentration (Tmax) of Azacitidine

End point description

Tmax was defined as the observed time to maximum plasma concentration of azacitidine. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: hours
median (full range (min-max))	0.083 (0.00 to 0.50)	0.083 (0.03 to 0.33)

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point (AUC0-t) of Azacitdine

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End point title

Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point (AUC0-t) of Azacitdine

End point description

AUC0-t was defined as the area under the plasma concentration-time curve from time zero to the last quantifiable time point, for azacitdine, calculated by the linear trapezoidal rule. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	629.069 ± 123.1	386.897 ± 149.4

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitdine

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End point title

Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitdine

End point description

Area under the plasma concentration-time curve from time 0 to 24 hours post-dose of azacitidine following multiple doses of azacitidine. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	634.840 ± 122.2	394.395 ± 145.9

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUC∞) of Azacitdine

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End point title

Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUC∞) of Azacitdine

End point description

Area under the plasma concentration-time curve from time zero to infinity, extrapolated to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity and was calculated according to the following equation: AUC∞ = AUCt + (Ct/λz), where Ct is the last quantifiable concentration. No AUC extrapolation will be performed with unreliable λz. If AUC% Ext is > 25%, AUC∞ will not be reported. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	9	12
Units: ng*h/mL
geometric mean (geometric coefficient of variation)	606.855 ± 131.6	240.212 ± 76.5

No statistical analyses for this end point

Secondary: Terminal Phase Half-life (t½) of Azacitidine

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End point title

Terminal Phase Half-life (t½) of Azacitidine

End point description

Terminal phase half-life, was calculated according to the following equation: t½ = 0.693/λz. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	9	12
Units: hours
geometric mean (geometric coefficient of variation)	0.433 ± 22.7	0.286 ± 58.4

No statistical analyses for this end point

Secondary: Apparent Total Plasma Clearance (CL/F) of Azacitdine

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End point title

Apparent Total Plasma Clearance (CL/F) of Azacitdine

End point description

Apparent total clearance, calculated as Dose/AUC∞. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	9	12
Units: L/h
geometric mean (geometric coefficient of variation)	166.434 ± 135.6	148.298 ± 104.2

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (Vz/F) of Azacitdine

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End point title

Apparent Volume of Distribution (Vz/F) of Azacitdine

End point description

Apparent volume of distribution of azacitdine was calculated according to the equation Vz = (CL)/λz . The PK population consisted of all subjects who received at least one dose of azacitidine and had at least one measurable concentration of azacitidine.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	9	12
Units: Liters
geometric mean (geometric coefficient of variation)	103.873 ± 122.0	61.119 ± 125.8

No statistical analyses for this end point

Secondary: Terminal Phase Rate Constant (λz) of Azacitdine

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End point title

Terminal Phase Rate Constant (λz) of Azacitdine

End point description

Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve. The pharmacokinetic evaluable population consisted of all subjects who received at least 1 dose of study drug and had at least 1 measurable concentration of study drug.

End point type

Secondary

End point timeframe

End point values	MDS: Azacitdine	JMML: Azacitidine
Number of subjects analysed	10	18
Units: L/h
geometric mean (geometric coefficient of variation)	1.822 ± 48.4	2.028 ± 83.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

MDS Cohort: Azacitidine

Reporting group description

Subjects with MDS received azacitidine 75 mg/m^2, either by intravenous infusion or by subcutaneous injection, on Days 1 to 7 of each 28-day treatment cycle for a minimum of 3 cycles and a maximum of 6 cycles, unless disease progression occurred.

Reporting group title

JMML Cohort: Azacitidine

Reporting group description

Subjects with JMML received azacitidine 75 mg/m^2, either by intravenous infusion or by subcutaneous injection, on Days 1 to 7 of each 28-day treatment cycle for a minimum of 3 cycles and a maximum of 6 cycles, unless disease progression occurred.

Serious adverse events	MDS Cohort: Azacitidine	JMML Cohort: Azacitidine
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 10 (40.00%)	12 / 18 (66.67%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Juvenile chronic myelomonocytic leukaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anaesthetic complication pulmonary
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Loss of consciousness
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	3 / 10 (30.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	5 / 8	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 10 (20.00%)	2 / 18 (11.11%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gingival bleeding
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Device related infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 10 (10.00%)	2 / 18 (11.11%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	MDS Cohort: Azacitidine	JMML Cohort: Azacitidine
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 10 (100.00%)	17 / 18 (94.44%)
Vascular disorders
Haematoma
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hypotension
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	2	1
Orthostatic hypotension
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
General disorders and administration site conditions
Catheter site pain
subjects affected / exposed	2 / 10 (20.00%)	0 / 18 (0.00%)
occurrences all number	2	0
Face oedema
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Fatigue
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Generalised oedema
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Malaise
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Oedema
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Oedema peripheral
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	4
Pyrexia
subjects affected / exposed	3 / 10 (30.00%)	10 / 18 (55.56%)
occurrences all number	4	33
Vessel puncture site haematoma
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Cough
subjects affected / exposed	1 / 10 (10.00%)	4 / 18 (22.22%)
occurrences all number	1	4
Dyspnoea
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Epistaxis
subjects affected / exposed	1 / 10 (10.00%)	2 / 18 (11.11%)
occurrences all number	2	5
Oropharyngeal pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Pharyngeal erythema
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Pleural effusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Respiratory distress
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Rhinorrhoea
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Tachypnoea
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Investigations
Blood albumin decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Blood fibrinogen decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
C-reactive protein increased
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Candida test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Enterococcus test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Staphylococcus test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Viral test positive
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Weight decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	2
Contusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Fall
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	2	0
Head injury
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Joint dislocation
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Post procedural haemorrhage
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Procedural pain
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Cardiac disorders
Pericardial effusion
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Pericarditis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Headache
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 10 (60.00%)	7 / 18 (38.89%)
occurrences all number	24	41
Coagulopathy
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Febrile neutropenia
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Hilar lymphadenopathy
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Histiocytosis haematophagic
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Leukocytosis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Leukopenia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	11	0
Lymphadenopathy
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	3
Lymphopenia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	5	0
Neutropenia
subjects affected / exposed	1 / 10 (10.00%)	3 / 18 (16.67%)
occurrences all number	1	3
Thrombocytopenia
subjects affected / exposed	4 / 10 (40.00%)	5 / 18 (27.78%)
occurrences all number	25	40
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Vertigo
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Eye disorders
Eye pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	5
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Ascites
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2
Constipation
subjects affected / exposed	3 / 10 (30.00%)	4 / 18 (22.22%)
occurrences all number	3	5
Diarrhoea
subjects affected / exposed	0 / 10 (0.00%)	4 / 18 (22.22%)
occurrences all number	0	9
Diarrhoea haemorrhagic
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Dysphagia
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Gingival bleeding
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Gingival hypertrophy
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Mouth haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Nausea
subjects affected / exposed	3 / 10 (30.00%)	2 / 18 (11.11%)
occurrences all number	3	3
Oral mucosal erythema
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Oral pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Periodontal disease
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Periodontal inflammation
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Proctalgia
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Rectal haemorrhage
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Stomatitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	2	0
Toothache
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Vomiting
subjects affected / exposed	3 / 10 (30.00%)	4 / 18 (22.22%)
occurrences all number	5	6
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hepatic failure
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Hyperbilirubinaemia
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	2	5
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	3
Dermatitis bullous
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Petechiae
subjects affected / exposed	1 / 10 (10.00%)	2 / 18 (11.11%)
occurrences all number	2	2
Pruritus
subjects affected / exposed	0 / 10 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	3
Pruritus generalised
subjects affected / exposed	1 / 10 (10.00%)	3 / 18 (16.67%)
occurrences all number	1	3
Rash
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2
Rash erythematous
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Rash macular
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2
Rash maculo-papular
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Rash papular
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Rash pruritic
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Urticaria
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Neck pain
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Pain in extremity
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	2	1
Infections and infestations
Anal candidiasis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Candida infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Clostridium difficile infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Conjunctivitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Dermatitis infected
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Febrile infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Nasopharyngitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Oral candidiasis
subjects affected / exposed	1 / 10 (10.00%)	1 / 18 (5.56%)
occurrences all number	1	1
Oral infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Otitis externa
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Parainfluenzae virus infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1
Respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Rhinitis
subjects affected / exposed	1 / 10 (10.00%)	2 / 18 (11.11%)
occurrences all number	1	2
Upper respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	2
Fluid retention
subjects affected / exposed	0 / 10 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	2
Hyperkalaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hyperuricaemia
subjects affected / exposed	0 / 10 (0.00%)	3 / 18 (16.67%)
occurrences all number	0	4
Hypoalbuminaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hypocalcaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hypokalaemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Hyponatraemia
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	4	0
Malnutrition
subjects affected / exposed	1 / 10 (10.00%)	0 / 18 (0.00%)
occurrences all number	1	0
Tumour lysis syndrome
subjects affected / exposed	0 / 10 (0.00%)	1 / 18 (5.56%)
occurrences all number	0	1

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Were there any global substantial amendments to the protocol? Yes

17 Dec 2014

As an added precaution to minimize harm, treatment discontinuation guidelines for subjects who, after 3 cycles, were responders to azacitidine and who had a neutrophil count below 0.5 × 10^9/L on Cycle 3 Day 28, or on Day 1 of Cycle 5 or 6. Subjects who met the criteria were to be discontinued from therapy and prepared for transplant. • A 14-day window was specified from diagnosis to the screening visit, was from the second (the latest) BM biopsy. The first BM exam did not need to be within 14 days of the screening visit. • In order to address regulatory concerns regarding blood volumes, the amount of blood collected for PK was reduced. Each collection time point required 1 mL of blood instead of 2 mL. For pediatric subjects who weighed ≤ 20 kg, to minimize blood collection for smaller children, only 5 time points were collected for PK assessments. • Reduced blood volumes for hematology and chemistry assessments from 2 mL to 1 mL at each time point. Removed requirement to draw 2 mL of blood for the PB smear slide. • Since the risk of disease transformation does not apply to JMML, the requirement for JMML subjects to have a BM aspirate within 14 days of the screening visit was removed. • Due to its rarity, subjects with NF-1 mutation without clinical symptoms were excluded. • Added instructions for storage of reconstituted AZA for SC administration for immediate use and for delayed use. Instructions for administration of reconstituted AZA for IV use was added to clarify the administration window for reconstituted product. • In order to address regulatory concerns for renal impairment, dose reduction guidelines based on fluctuations in serum creatinine were added. • Modified the revised Cheson IWG response criteria in order to adapt the criteria to children. • Added definition of relapse after HSCT in children with JMML to the current JMML response criteria. • Removed vaccinations from the list of prohibited medications and added to the list of permitted medications.

12 May 2015

• Clarified IV administration of AZA as preferred route over SC route. • Added rationale for selecting the dose of 75 mg/m2. • Amended secondary endpoint of treatment-related AEs to TEAEs. • Added 14-day visit window to Day 1 of Cycles 2 to 6. • Clarified pregnancy testing requirements. Clarified that female and male subjects who reached 18 years while on study must have agreed to undergo physician-approved sex education at specified time points.• Specified the pre-HSCT hematology assessments were to be performed only if > 21 days since the last hematology assessment. • Corrected footnotes in Table of Events related to JMML response categories and corrected timing text of BM aspirates for mutational analysis. • Specified that PEs were to include evaluation for PD for JMML subjects in order to evaluate patients according to current JMML response criteria. • Removed statement related to catheter flushing prior to PK sampling. • Added acceptable deviation windows to PK sampling schedules. • In response to regulatory concerns, the barrier method in combination with spermicide was removed as a contraceptive method. • Specified IV dosing of AZA was required to be completed within 45 minutes instead of 60 minutes. • Specified that AZA was incompatible with 5% dextrose. • Clarified subjects with delayed treatment due to renal toxicity were an exception to starting the 2nd or 3rd cycles of treatment no later than 42 days after Day 1 of the previous cycle since these subjects may require more time for renal function to return to baseline values. • Clarified safety data will not be presented for the historical controls. • Revised text to distinguish treatment discontinuation and study discontinuation. • Clarified amendments were to be submitted to the IEC and regulatory authorities for written approval in accordance with legal requirements. • Improved language regarding compliance with Celgene publication policy and included language regarding public website/registry posting.

06 Aug 2018

• The long-term follow-up was reduced to 1 year from the last dose of IP instead of 2 years as 1 year of information post last dose would allow sufficient time to follow the patients through HSCT and also provided sufficient post HSCT survival and safety information during follow up. • Clarified that as the matched-pairs analysis was not viable due to a lack of key data critical to establish pairing of subject which was central to the analysis, other methodologies were explored to allow evaluation of response rates which were either reported in available literature or identified in patient registry database(s). Further analyses would have looked to compare response rates in subjects who received other therapy(ies) in this disease setting. • Clarified the language on the dilution volume of azacitidine and updated suggested infusion dilution volumes to align with the protocol clarification letter that was provided to sites on 25 Aug 2015. • Updated the title s for the Clinical Research Scientist contacts.

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.

As fewer than 2 MDS subjects had a response after stage 1, enrollment was closed. For the JMML arm, the threshold of confirmed responses was met with 9 subjects achieving a confirmed clinical response. Hence, Stage 2 was not executed for the JMML arm

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: MDS Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

Primary: MDS Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

Primary: JMML Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

Primary: JMML Cohort: Percentage of Subjects with a Confirmed Response at Cycle 3, Day 28 Based on Central Review

Secondary: MDS Cohort: Number of Subjects who Achieved a Cytogenetic Response at Cycle 3 Day 28 Based on Central Review

Secondary: MDS Cohort: Number of Subjects who Achieved a Cytogenetic Response at Cycle 3 Day 28 Based on Central Review

Secondary: JMML Cohorts: Number of Subjects who Achieved a Genetic and Molecular Response at Cycle 3 Day 28 Based on Central Review

Secondary: JMML Cohorts: Number of Subjects who Achieved a Genetic and Molecular Response at Cycle 3 Day 28 Based on Central Review

Secondary: MDS Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

Secondary: MDS Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

Secondary: JMML Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

Secondary: JMML Cohort: Kaplan-Meier Estimate of Duration of Response Based on Central Review

Secondary: MDS Cohort: Time to Response Based on Central Review

Secondary: MDS Cohort: Time to Response Based on Central Review

Secondary: JMML Cohort: Time to Response Based on Central Review

Secondary: JMML Cohort: Time to Response Based on Central Review

Secondary: MDS Cohort: Kaplan Meier Estimate of Time to Progression

Secondary: MDS Cohort: Kaplan Meier Estimate of Time to Progression

Secondary: JMML Cohort: Kaplan Meier Estimate of Time to Progression

Secondary: JMML Cohort: Kaplan Meier Estimate of Time to Progression

Secondary: MDS Cohort: Kaplan Meier Estimate of Leukemia-Free Survival (LFS)

Secondary: MDS Cohort: Kaplan Meier Estimate of Leukemia-Free Survival (LFS)

Secondary: JMML Cohort: Kaplan Meier Estimate of Leukemia-Free Survival

Secondary: JMML Cohort: Kaplan Meier Estimate of Leukemia-Free Survival

Secondary: MDS Cohort: Kaplan Meier Estimate of Overall Survival

Secondary: MDS Cohort: Kaplan Meier Estimate of Overall Survival

Secondary: JMML Cohort: Kaplan Meier Estimate of Overall Survival

Secondary: JMML Cohort: Kaplan Meier Estimate of Overall Survival

Secondary: MDS Cohort: Percentage of Subjects Who Received a Hematopoietic Stem Cell Transplant (HSCT)

Secondary: MDS Cohort: Percentage of Subjects Who Received a Hematopoietic Stem Cell Transplant (HSCT)

Secondary: JMML Cohort: Percentage of Subjects Who Received a HSCT

Secondary: JMML Cohort: Percentage of Subjects Who Received a HSCT

Secondary: MDS Cohort: Time to First Hematopoietic Stem Cell Transplant

Secondary: MDS Cohort: Time to First Hematopoietic Stem Cell Transplant

Secondary: JMML Cohort: Time to First Hematopoietic Stem Cell Transplant

Secondary: JMML Cohort: Time to First Hematopoietic Stem Cell Transplant

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

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

Secondary: Maximum Plasma Concentration (Cmax) of Azacitidine

Secondary: Maximum Plasma Concentration (Cmax) of Azacitidine

Secondary: Time to Maximum Plasma Concentration (Tmax) of Azacitidine

Secondary: Time to Maximum Plasma Concentration (Tmax) of Azacitidine

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point (AUC0-t) of Azacitdine

Secondary: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point (AUC0-t) of Azacitdine

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitdine

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitdine

Secondary: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUC∞) of Azacitdine

Secondary: Area Under the Plasma Concentration-time Curve from Time Zero to Infinity (AUC∞) of Azacitdine

Secondary: Terminal Phase Half-life (t½) of Azacitidine

Secondary: Terminal Phase Half-life (t½) of Azacitidine

Secondary: Apparent Total Plasma Clearance (CL/F) of Azacitdine

Secondary: Apparent Total Plasma Clearance (CL/F) of Azacitdine

Secondary: Apparent Volume of Distribution (Vz/F) of Azacitdine

Secondary: Apparent Volume of Distribution (Vz/F) of Azacitdine

Secondary: Terminal Phase Rate Constant (λz) of Azacitdine

Secondary: Terminal Phase Rate Constant (λz) of Azacitdine

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information