Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12610000271000
Ethics application status
Approved
Date submitted
18/03/2010
Date registered
1/04/2010
Date last updated
4/08/2023
Date data sharing statement initially provided
16/01/2020
Date results information initially provided
16/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Lenalidomide and 5azacitidine treatment versus 5azacitidine alone in patients with the blood cancers myelodysplastic syndrome or acute myeloid leukaemia
Scientific title
A Randomised Phase II study comparing the efficacy of 5azacitidine alone versus combination therapy with lenalidomide and 5azacitidine in patients with higher risk myelodysplastic syndromes (MDS) and low marrow blast count acute myeloid leukaemia (AML).
Secondary ID [1] 1464 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelodysplastic syndromes (MDS) 256919 0
Low marrow blast count acute myeloid leukaemia (AML) 256920 0
Condition category
Condition code
Blood 257067 257067 0 0
Haematological diseases
Cancer 257182 257182 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
combination 5azacitidine (subcutaneous administration) and oral lenalidomide. All patients begin 5azacitidine 75mg/m2/day x 7 days (75mg/m2/day on days 1-5 and days 8-9) of a 28 day cycle. At Cycle 3, patients are randomised to commence lenalidomide (at 10mg/day x 21 days of a 28 day cycle) in combination with 5 azacitidine (75mg/m2/day x 5 days (days 1-5) of a 28 day cycle) until primary endpoint at 12 months after commencing treatment. Following this, all patients may continue 5azacitidine alone until progression or toxicity.
Intervention code [1] 256115 0
Treatment: Drugs
Comparator / control treatment
5azacitidine alone (subcutaneous administration; 75mg/m2/day on days 1-5 and days 8-9 of each 28 day cycle) for 12 months until primary endpoint, then all patients may continue 5azacitidine alone until progression or toxicity.
Control group
Active

Outcomes
Primary outcome [1] 257962 0
To demonstrate improved efficacy with the combination of lenalidomide and 5azacitidine compared to 5azacitidine alone in patients with MDS and low marrow blast count AML, with acceptable toxicity of the combination. Outcome will be assessed by measures of disease response as defined by International Working Group (IWG) criteria (2006) and determined by peripheral blood counts, transfusions, bone marrow morphology and cytogenetics.
Timepoint [1] 257962 0
12 months from start of treatment
Secondary outcome [1] 263493 0
To describe responses, duration of response and overall survival with 5azacitidine or lenalidomide + 5azacitidine in patients with MDS and low marrow blast count AML. Outcome will be assessed by measures of disease response as defined by International Working Group (IWG) criteria (2006) and determined by peripheral blood counts, transfusions, bone marrow morphology and cytogenetics.
Timepoint [1] 263493 0
2 years after last accrued patient completes study treatment
Secondary outcome [2] 263494 0
To describe tolerability of the combination of lenalidomide and 5azacitidine in patients with MDS and low marrow blast count AML. Outcome will be assessed by rate of non-haematological adverse events and a protocol-specific definition of haematologic toxicity. These events will be documented by clinicians during clinic visits.
Timepoint [2] 263494 0
2 years after last accrued patient completes study treatment
Secondary outcome [3] 263495 0
To explore biomarkers of response and mechanism of action of 5azacitidine and lenalidomide in patients with MDS and low marrow blast count AML using a variety of correlative studies at baseline and on treatment correlated to individual clinical responses
Timepoint [3] 263495 0
2 years after last accrued patient completes study treatment

Eligibility
Key inclusion criteria
Disease diagnosis of either MDS (by World Health Organisation criteria, those with refractory anaemia and Refractory Anaemia with Ringed Sideroblasts to also have at least one clinically significant cytopenia), nonproliferative Chronic Myelomonocytic Leukaemia (CMML) or low marrow blast count AML; Eastern Cooperative Oncology Group (ECOG) 2 or less with life expectancy at least 3 months, adequate contraception and adequate renal and hepatic function, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Prior chemotherapy for MDS or AML except low dose cytarabine or hydroxyurea, any prior demethylating agent or immunomodulatory drug (including thalidomide or lenalidomide), prior diagnosis of cancer except with low risk of recurrence, significant renal, hepatic, cardiac or respiratory disease or severe active infection.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Subjects will be registered and randomised at a central administration site. The clinician at the study site who assesses study eligibility as per protocol criteria is unaware prior to the randomisation procedure, which study arm the subject will be allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
a dynamic computer-based minimisation algorithm will be used to determine approximately equal (1:1 ratio) numbers of patients to each arm (AZA+/- LEN), with stratification by International Prognostic Scoring System (low-int1 or int2-high)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/08/2010
Actual
9/03/2011
Date of last participant enrolment
Anticipated
Actual
12/03/2013
Date of last data collection
Anticipated
Actual
31/08/2016
Sample size
Target
160
Accrual to date
Final
160
Recruitment in Australia
Recruitment state(s)
NSW,VIC,ACT,QLD,SA,WA,NT,TAS
Recruitment outside Australia
Country [1] 2534 0
New Zealand
State/province [1] 2534 0

Funding & Sponsors
Funding source category [1] 256611 0
Commercial sector/Industry
Name [1] 256611 0
Celgene Pty Ltd
Country [1] 256611 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Level 2/10 St Andrews Place
East Melbourne, Victoria, Australia, 3002
Country
Australia
Secondary sponsor category [1] 255902 0
None
Name [1] 255902 0
Address [1] 255902 0
Country [1] 255902 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 258641 0
Sir Charles Gairdner Group HREC
Ethics committee address [1] 258641 0
Sir Charles Gairdner Hospital
2nd Floor A Block
Hospital Avenue
NEDLANDS Western Australia 6009
Ethics committee country [1] 258641 0
Australia
Date submitted for ethics approval [1] 258641 0
07/12/2010
Approval date [1] 258641 0
03/03/2011
Ethics approval number [1] 258641 0
Ethics committee name [2] 297800 0
AUSTIN HEALTH HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [2] 297800 0
145 Studley Rd, Heidelberg VIC 3084
Ethics committee country [2] 297800 0
Australia
Date submitted for ethics approval [2] 297800 0
01/11/2010
Approval date [2] 297800 0
13/12/2010
Ethics approval number [2] 297800 0
HREC/10/Austin/49
Ethics committee name [3] 305123 0
Northern Sydney Central Coast Health (NSCCH) HREC
Ethics committee address [3] 305123 0
NSLHD Research Office, Level 13 Kolling Building, Royal North Shore Hospital, Reserve Road, St Leonards, NSW, 2065
Ethics committee country [3] 305123 0
Australia
Date submitted for ethics approval [3] 305123 0
26/11/2010
Approval date [3] 305123 0
13/01/2011
Ethics approval number [3] 305123 0
HREC/10/HAWKE/134
Ethics committee name [4] 305124 0
Flinders university human ethics committee
Ethics committee address [4] 305124 0
Flinders Medical
Centre
The Flats G5 –
Rooms 3 and 4
Flinders Drive,
Bedford Park
SA 5042
Ethics committee country [4] 305124 0
Australia
Date submitted for ethics approval [4] 305124 0
04/12/2010
Approval date [4] 305124 0
01/03/2011
Ethics approval number [4] 305124 0
SAC HREC EC00188
Ethics committee name [5] 305125 0
ACT Health Human Research Ethics Committee
Ethics committee address [5] 305125 0
Building 10, Level 6, ACT Health Research Office, Canberra Hospital ACT 2605
Ethics committee country [5] 305125 0
Australia
Date submitted for ethics approval [5] 305125 0
04/01/2011
Approval date [5] 305125 0
22/03/2011
Ethics approval number [5] 305125 0
ETH.2.11.017
Ethics committee name [6] 305126 0
South Metropolitan Health Service Human Research Ethics Committee ( -
Ethics committee address [6] 305126 0
Alma Street Fremantle Western Australia 6160
Ethics committee country [6] 305126 0
Australia
Date submitted for ethics approval [6] 305126 0
15/03/2011
Approval date [6] 305126 0
05/05/2011
Ethics approval number [6] 305126 0
11/74
Ethics committee name [7] 305127 0
Greenslopes Private Hospital HREC
Ethics committee address [7] 305127 0
Greenslopes Private Hospital
Newdegate Street
Greenslopes Qld 4120
Ethics committee country [7] 305127 0
Australia
Date submitted for ethics approval [7] 305127 0
11/01/2011
Approval date [7] 305127 0
24/03/2011
Ethics approval number [7] 305127 0
10/21
Ethics committee name [8] 305128 0
BELLBERRY HUMAN RESEARCH ETHICS COMMITTEE
Ethics committee address [8] 305128 0
129 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [8] 305128 0
Australia
Date submitted for ethics approval [8] 305128 0
24/11/2010
Approval date [8] 305128 0
17/02/2011
Ethics approval number [8] 305128 0
2010-10-551
Ethics committee name [9] 305129 0
Metro South Health Service District Human Research Ethics Committee
Ethics committee address [9] 305129 0
Metro South Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [9] 305129 0
Australia
Date submitted for ethics approval [9] 305129 0
14/06/2011
Approval date [9] 305129 0
25/08/2011
Ethics approval number [9] 305129 0
HREC/10/QPAH/286
Ethics committee name [10] 305130 0
Royal Adelaide Hospital Research Ethics Committee
Ethics committee address [10] 305130 0
Royal Adelaide Hospital Human Research Ethics Committee
Level 3, Hanson Institute, IMVS Building
Royal Adelaide Hospital
North Terrace Adelaide, South Australia, 5000
Ethics committee country [10] 305130 0
Australia
Date submitted for ethics approval [10] 305130 0
27/11/2010
Approval date [10] 305130 0
31/01/2011
Ethics approval number [10] 305130 0
101212

Summary
Brief summary
Lenalidomide and Azacitidine each have clear evidence of efficacy in MDS, and have shown activity in AML. However, not all patients respond so better regimens, including combinations, are required. MDS and AML are heterogeneous diseases, and lenalidomide and azacitidine may target different cellular populations and induce differing clinical responses. Combinations of immunomodulatory drugs and azacitidine have been explored and shown to be feasible. This is an open label, multi-centre, randomised Phase II study exploring the toxicity and efficacy of the combination of lenalidomide and 5azacitidine compared to 5azacitidine alone. After an initial 2 cycles with 5azacitidine (75mg/m2/day x7days over 9days of a 28 day cycle; 5-2-2 regimen), patients will be randomised 1:1 to either combination 5azacitidine and lenalidomide (5azacitidine 75mg/m2/day x5days of a 28 day cycle + lenalidomide commencing cycle 3 10mg/dayx21days of a 28 day cycle) or 5azacitidine alone (75mg/m2/day x7days over 9days of a 28 day cycle; 5-2-2 regimen) for 12 months to primary endpoint, then all patients may continue 5azacitidine alone until progression or toxicity. Response will be determined by peripheral blood counts, transfusions, bone marrow morphology and cytogenetics, according to IWG criteria. The study also incorporates a correlative laboratory component designed to determine the mechanism of action of 5azacitidine +/- lenalidomide and to determine a baseline profile which may predict those most responsive. These studies will incorporate gene methylation and expression, and enumeration of lymphocyte subsets, natural killer cell function and cytokine profiles.
Trial website
Trial related presentations / publications
Haematologica 2019 Volume 104(4):700-709
Public notes

Contacts
Principal investigator
Name 30905 0
Dr Melita Kenealy
Address 30905 0
Cabrini Haematology & Oncology Centre
Level 2, 183 Wattletree Road
Malvern VIC 3144
Australia
Country 30905 0
Australia
Phone 30905 0
+61 417 566 902
Fax 30905 0
Email 30905 0
melita.kenealy@thebloodunit.com.au
Contact person for public queries
Name 14152 0
Dr Dr Melita Kenealy
Address 14152 0
Cabrini Haematology & Oncology Centre
Level 2, 183 Wattletree Road
Malvern VIC 3144
Australia
Country 14152 0
Australia
Phone 14152 0
+61 417 566 902
Fax 14152 0
Email 14152 0
melita.kenealy@thebloodunit.com.au
Contact person for scientific queries
Name 5080 0
Dr Dr Melita Kenealy
Address 5080 0
Cabrini Haematology & Oncology Centre
Level 2, 183 Wattletree Road
Malvern VIC 3144
Australia
Country 5080 0
Australia
Phone 5080 0
+61 417 566 902
Fax 5080 0
Email 5080 0
melita.kenealy@thebloodunit.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data, for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.
Available for what types of analyses?
Any type of analysis
Assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to info@allg.org.au


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19920Study protocol  info@allg.org.au Access can be requested via the Health Data Austra... [More Details]



Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Haematologica 2019 Volume 104(4):700-709 335226-(Uploaded-02-01-2020-09-51-41)-Journal results publication.pdf

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseAzacitidine with or without lenalidomide in higher risk myelodysplastic syndrome & low blast acute myeloid leukemia.2019https://dx.doi.org/10.3324/haematol.2018.201152
EmbaseFavorable outcomes of DDX41-mutated myelodysplastic syndrome and low blast count acute myeloid leukemia treated with azacitidine +/- lenalidomide.2023https://dx.doi.org/10.1002/jha2.767
N.B. These documents automatically identified may not have been verified by the study sponsor.