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Clinical Trial Results:
A multicentre open randomized phase II study of the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q)

Summary
EudraCT number	2011-001639-21
Trial protocol	SE FI NO DK
Global end of trial date	29 Aug 2020

Results information
Results version number	v1(current)
This version publication date	12 Jun 2024
First version publication date	12 Jun 2024
Other versions

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

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Sponsor protocol code

NMDSG10B

ISRCTN number

US NCT number

NCT01556477

WHO universal trial number (UTN)

Sponsor organisation name

Nordic MDS Group

Sponsor organisation address

Karolinska University Hospital Huddinge, Stockholm, Sweden, 14186

Public contact

Lars Möllgård, Sahlgrenska University Hospital, Postcode 41345, Gothenburg, Sweden, , +46 31 3420000, lars.mollgard@vgregion.se

Scientific contact

Eva Hellström-Lindberg, Karolinska University Hospital Huddinge, +46 8 858580000, lars.mollgard@karolinska.se

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

20 Aug 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

29 Aug 2017

Global end of trial reached?

Yes

Global end of trial date

29 Aug 2020

Was the trial ended prematurely?

Main objective of the trial

To study the efficacy of azacitidine with or without the additioiin of lenalidomide in high-risk MDS (IPSS Int-2 or high) and AML (multilineage dysplasia and 20-30% marrow blasts) with a karyotype oncluding del(5q)

Protection of trial subjects

For the experimental arm with azacitidine + lenalidomide ther we were aware of a higher risk of inectious complications. To avoid this there was a possibility to add GCS-F treatment if neutrofils were low.

Background therapy

All patients received the standard treatment for this group of patient with sc azacitidine.

Evidence for comparator

Azacitidine i standard treatment for patients with both MDS and AML

Actual start date of recruitment

01 Dec 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Norway: 7

Country: Number of subjects enrolled

Sweden: 53

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

Finland: 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

The patients were recruited between 7 March 2012 and 29 August 2017 in Sweden, Denmark, Norway and Finland.

Screening details

The patients were screened during a 28 days period. There were 19 screen failures (8 patients with >30% blasts in the bone marrow, 6 patients with no 5q deletion, 2 patients with IPSS score intremediate 1, 2 patients with rapid progression and 1 patient due to patient request.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

azacitidine

Arm description

Standard dose of azacitidine 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks and 6 cycles

Arm type

Active comparator

Investigational medicinal product name

azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

azacitidine 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks

azacitidine + lenalidomide

Arm description

Standard dose of AZA 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks + lenalidomide 10 mg, oral, daily, 21/28 days, starting day one in each azacitidine cycle and leaving the last week free of treatment. If tolerated, the dose was escalated to 25 mg daily during cycle four to six.

Arm type

Experimental

Investigational medicinal product name

azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

azacitidine 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks

Investigational medicinal product name

lenalidomide

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

The initial dose of lenalidomide was 10 mg, oral, daily, 21/28 days, starting day one in each azacitidine cycle and leaving the last week free of treatment. If tolerated, the dose was escalated to 25 mg daily during cycle four to six.

Number of subjects in period 1	azacitidine	azacitidine + lenalidomide
Started	36	36
Completed	21	19
Not completed	15	17
Treatment not started	3	-
Consent withdrawn by subject	-	2
Disease progression	6	2
Adverse Event	6	10
Did not start tretament	-	3

Baseline characteristics

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Reporting group title

azacitidine

Reporting group description

Standard dose of azacitidine 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks and 6 cycles

Reporting group title

azacitidine + lenalidomide

Reporting group description

Reporting group values	azacitidine	azacitidine + lenalidomide	Total
Number of subjects	36	36	72
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)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	11	10	21
From 65-84 years	25	26	51
85 years and over	0	0	0
Age continuous
Units: years
median (full range (min-max))	73 (35 to 82)	70 (37 to 84)	-
Gender categorical
Units: Subjects
Female	16	14	30
Male	20	22	42

Subject analysis set title

Intention to treat group

Subject analysis set type

Intention-to-treat

Subject analysis set description

The subjects who were included in the study on an intentions to treat basis

Subject analysis sets values	Intention to treat group
Number of subjects	72
Age categorical
Units: Subjects
In utero	0
Preterm newborn infants (gestational age < 37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	21
From 65-84 years	51
85 years and over	0
Age continuous
Units: years
median (full range (min-max))	71 (35 to 84)
Gender categorical
Units: Subjects
Female	30
Male	42

End points

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Reporting group title

azacitidine

Reporting group description

Standard dose of azacitidine 5-2-2 (75 mg/m2/day subcutaneously12) with a total cycle length of 4 weeks and 6 cycles

Reporting group title

azacitidine + lenalidomide

Reporting group description

Subject analysis set title

Intention to treat group

Subject analysis set type

Intention-to-treat

Subject analysis set description

The subjects who were included in the study on an intentions to treat basis

Primary: response according to 2006 International Working Group (IWG) criteria for MDS13

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End point title

response according to 2006 International Working Group (IWG) criteria for MDS13

End point description

The primary endpoint, was response according to 2006 International Working Group (IWG) criteria for MDS13, was assessed by two independent observers after six cycles of AZA or AZA+LEN treatment, or at end of study if this occurred at an earlier time point.

End point type

Primary

End point timeframe

The Primary endpoint was assessed after six cycles of azacitidine or azacitidine+lenalidmode treatment, or at end of study if this occurred at an earlier time point.

End point values	azacitidine	azacitidine + lenalidomide	Intention to treat group
Number of subjects analysed	33	33	66
Units: Number of patients
number (not applicable)	14	16	30

Statistical evaluation of response

Statistical analysis description

Continuous data were described by mean and median (range) values depending on the distribution of data. 2- or Fisher´s exact tests were used to measure the difference between responders and non-responders.

Comparison groups

azacitidine v azacitidine + lenalidomide

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.62

Method

Fisher exact

Confidence interval

Adverse events

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Timeframe for reporting adverse events

All AEs will be recorded by the Investigator(s) from the time the subject signs informed consent through the end of the designated follow-up period

Assessment type

Non-systematic

Dictionary name

NCI CTCAE

Dictionary version

4.03

Reporting group title

Azacitidine arm

Reporting group description

Reporting group title

Azacitidin + lenalidomide arm

Reporting group description

Serious adverse events	Azacitidine arm	Azacitidin + lenalidomide arm
Total subjects affected by serious adverse events
subjects affected / exposed	33 / 33 (100.00%)	33 / 33 (100.00%)
number of deaths (all causes)	6	0
number of deaths resulting from adverse events	2	0
Cardiac disorders
Heart failure
subjects affected / exposed	0 / 33 (0.00%)	4 / 33 (12.12%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 2
Nervous system disorders
Subarachnoid haematoma, cerebral hematoma
subjects affected / exposed	1 / 33 (3.03%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 1
Blood and lymphatic system disorders
Severe myelosupression
subjects affected / exposed	28 / 33 (84.85%)	31 / 33 (93.94%)
occurrences causally related to treatment / all	28 / 28	31 / 31
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	27 / 33 (81.82%)	24 / 33 (72.73%)
occurrences causally related to treatment / all	27 / 27	24 / 24
deaths causally related to treatment / all	0 / 0	0 / 0
Anemia
subjects affected / exposed	16 / 33 (48.48%)	13 / 33 (39.39%)
occurrences causally related to treatment / all	16 / 16	13 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	25 / 33 (75.76%)	18 / 33 (54.55%)
occurrences causally related to treatment / all	25 / 25	18 / 18
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Fever
subjects affected / exposed	2 / 33 (6.06%)	4 / 33 (12.12%)
occurrences causally related to treatment / all	2 / 2	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 33 (6.06%)	1 / 33 (3.03%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 33 (3.03%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sweets syndrome
subjects affected / exposed	2 / 33 (6.06%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Febrile neutropenia
subjects affected / exposed	11 / 33 (33.33%)	15 / 33 (45.45%)
occurrences causally related to treatment / all	11 / 11	15 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	8 / 33 (24.24%)	7 / 33 (21.21%)
occurrences causally related to treatment / all	8 / 8	7 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 33 (3.03%)	5 / 33 (15.15%)
occurrences causally related to treatment / all	1 / 1	5 / 5
deaths causally related to treatment / all	1 / 1	4 / 4
Sepsis
subjects affected / exposed	3 / 33 (9.09%)	6 / 33 (18.18%)
occurrences causally related to treatment / all	0 / 3	0 / 6
deaths causally related to treatment / all	0 / 1	0 / 4
Fungal infection
subjects affected / exposed	3 / 33 (9.09%)	0 / 33 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
perianal infection
subjects affected / exposed	0 / 33 (0.00%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary aspergillosis
subjects affected / exposed	0 / 33 (0.00%)	2 / 33 (6.06%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Azacitidine arm	Azacitidin + lenalidomide arm
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 33 (100.00%)	33 / 33 (100.00%)
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	29 / 33 (87.88%)	26 / 33 (78.79%)
occurrences all number	29	26
Anemia
subjects affected / exposed	26 / 33 (78.79%)	29 / 33 (87.88%)
occurrences all number	26	29
Thrombocytopenia
subjects affected / exposed	21 / 33 (63.64%)	28 / 33 (84.85%)
occurrences all number	21	28
General disorders and administration site conditions
Nausea
subjects affected / exposed	3 / 33 (9.09%)	9 / 33 (27.27%)
occurrences all number	3	9
Gastrointestinal disorders
Constipation
subjects affected / exposed	8 / 33 (24.24%)	13 / 33 (39.39%)
occurrences all number	8	13
Diarrhoea
subjects affected / exposed	5 / 33 (15.15%)	7 / 33 (21.21%)
occurrences all number	5	7
Skin and subcutaneous tissue disorders
Injection site reaction
subjects affected / exposed	7 / 33 (21.21%)	6 / 33 (18.18%)
occurrences all number	7	6
Rash
subjects affected / exposed	4 / 33 (12.12%)	7 / 33 (21.21%)
occurrences all number	4	7
Infections and infestations
Febrile neutropenia
subjects affected / exposed	11 / 33 (33.33%)	15 / 33 (45.45%)
occurrences all number	11	15
Pneumonia
subjects affected / exposed	9 / 33 (27.27%)	9 / 33 (27.27%)
occurrences all number	9	9
Infection
subjects affected / exposed	1 / 33 (3.03%)	8 / 33 (24.24%)
occurrences all number	1	8
Sepsis
subjects affected / exposed	3 / 33 (9.09%)	6 / 33 (18.18%)
occurrences all number	3	6
Urinary tract infection
subjects affected / exposed	6 / 33 (18.18%)	2 / 33 (6.06%)
occurrences all number	6	2

More information

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Were there any global substantial amendments to the protocol? Yes

16 Nov 2011

The approved CTA contains only one dose, 10 mg, of the comparator IMP, lenalidomide. According to the approved study protocol, a 25 mg dose of lenalidomide will also be used. The CTA has therefore been amended accordingly with acorrected MA number for the 10 mg

23 Apr 2012

The manufacturer of Lenalidomide has changed from Fischer to Almac and the package has changed from bottles to blisters, now available as a market product. The corresponding changes have been added to a revised CTA form (EudraCT v8).

13 Jun 2016

Due to slow inclusion rate we have decided during the last year to include patients who have had a maximum of 1 cycle of azacitidine before inclusion. So far every potential study object in that situation has been discussed with the study committee and noted as protocol violence in the CRF. In amendment 4 the exclusion criteria will be changed from: “Prior therapy with azacitidine” to “Prior therapy with >1 cycle of azacitidine”.

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

http://www.ncbi.nlm.nih.gov/pubmed/35277655

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Clinical trials

Clinical Trial Results:
A multicentre open randomized phase II study of the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: response according to 2006 International Working Group (IWG) criteria for MDS13

Primary: response according to 2006 International Working Group (IWG) criteria for MDS13

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical trials

Clinical Trial Results: A multicentre open randomized phase II study of the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: response according to 2006 International Working Group (IWG) criteria for MDS13

Primary: response according to 2006 International Working Group (IWG) criteria for MDS13

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
A multicentre open randomized phase II study of the efficacy and safety of azacitidine alone or in combination with lenalidomide in high-risk myeloid disease (high-risk MDS and AML) with a karyotype including del(5q)