Phase II study of combination therapy with 5-AZAcytidine, Valproic acid, and All-Trans Retinoic Acid in patients with myelodysplastic syndromes and other myeloid malignancies who cannot receive intensive chemotherapy

ISRCTN	ISRCTN92868457
DOI	https://doi.org/10.1186/ISRCTN92868457
EudraCT/CTIS number	2005-004454-27
Secondary identifying numbers	AZAVATRA _V01

Submission date: 28/03/2007
Registration date: 19/07/2007
Last edited: 28/10/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Norbert Gattermann
Scientific

Department of Haematology, Oncology and Clinical Immunology
Moorenstrasse 5
Duesseldorf
40225
Germany

Study information

Study design	Phase II, open, prospective, single-armed, multicentre trial.
Primary study design	Interventional
Secondary study design	Multi-centre
Study setting(s)	Hospital
Study type	Treatment
Scientific title	Phase II study of combination therapy with 5-AZAcytidine, Valproic acid, and All-Trans Retinoic Acid in patients with myelodysplastic syndromes and other myeloid malignancies who cannot receive intensive chemotherapy
Study acronym	AZAVATRA
Study objectives	Myelodysplastic Syndromes (MDS) are acquired clonal bone marrow disorders, characterised by impaired maturation and dysplastic morphology of haematopoietic precursor cells. Patients with MDS suffer from ineffective haematopoesis, causing anaemia, infectious complications, and haemorrhagic diathesis. Leukaemic transformation occurs in about 25% of cases. In vitro studies suggest that combining two principles of epigenetic treatment, namely reversal of Deoxyribonucleic Acid (DNA) promoter hypermethylation by inhibitors of DNA methyltransferases, and reversal of chromatin condensation by histone acetylase inhibitors, synergize in reversing abnormal gene silencing. The principal question of this clinical trial is to test whether the in vitro findings can be translated into therapeutic success in vivo.
Ethics approval(s)	Approval received from the Ethics Committee of the medical faculty of the Heinrich-Heine-University (leading) and the Ethics Committee of medical faculty of the Johann-Wolfgang-Goethe University on the 22nd June 2006 (ref: MC-LKP-107).
Health condition(s) or problem(s) studied	Myelodysplastic syndromes (MDS)
Intervention	Epigenetic treatment of MDS with demethylating agents has achieved remarkable clinical responses and seems to be superior to supportive care or intensive chemotherapy. Low-dose 5-azacytidine was the first drug shown to alter the natural course of MDS by significantly prolonging the time until leukaemia transformation. At our institute we tried a different type of epigenetic treatment when we conducted the first clinical trial with Valproic Acid (VPA) in MDS. This drug has been shown to act as an inhibitor of Histone Deacetylase (HDAC). Since HDAC inhibitors and demethylating agents show synergistic effects in vitro, it appears promising to try the combination in vivo. The differentiation-inducing agent All-Trans Retinoic Acid (ATRA) will be added after four months if 5-Aza plus VPA do not produce a satisfactory treatment response. The treatment was as follows: 1. From beginning: Valproic acid 1500 - 2000 mg/d over one year, and azacytidine 100 mg/m^2/d applied over five days repeated every 28 days 2. After four months (if no improvement): All-trans retinoic acid 80 mg/m^2/d day one to seven repeated every 14 days
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	5-Azacytidine (5-Aza), Valproic Acid (VPA), and All-Trans Retinoic Acid (ATRA)
Primary outcome measure	Safety/toxicity, assessed at one year after treatment start.
Secondary outcome measures	All endpoints will be assessed at one year after treatment start: 1. Haematological response 2. Progression-free survival 3. Overall survival
Overall study start date	19/03/2007
Completion date	01/05/2010

Eligibility

Participant type(s)	Patient
Age group	Not Specified
Sex	Not Specified
Target number of participants	25
Total final enrolment	24
Key inclusion criteria	1. Primary Myelodysplastic Syndromes (pMDS) with unfavourable risk profile (more than 10% blast cells in the bone marrow, unfavourable karyotype) 2. Therapy-related (secondary) Myelodysplastic Syndromes (sMDS) 3. Chronic Myelomonocytic Leukaemia (CMML) 4. De-novo or secondary acute myeloid leukemia in elderly patients who cannot be treated with intensive chemotherapy
Key exclusion criteria	1. Impaired liver or kidney function 2. Pregnancy 3. Simultaneous participation in another clinical trial
Date of first enrolment	19/03/2007
Date of final enrolment	01/05/2010

Locations

Countries of recruitment

Germany

Study participating centre

Department of Haematology, Oncology and Clinical Immunology

Duesseldorf
40225
Germany

Sponsor information

Heinrich-Heine-University (Germany)
University/education

c/o Professor N Gattermann
Department of Haematology, Oncology and Clinical Immunology
Moorenstrasse 5
Duesseldorf
40225
Germany

Website	http://www.uni-duesseldorf.de/
"ROR"	https://ror.org/024z2rq82

Funders

Funder type

University/education

Heinrich-Heine-University (Germany)

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Basic results		05/02/2020	28/10/2021	No	No

Editorial Notes

28/10/2021: The following changes have been made:
1. The basic results of this trial have been uploaded as an additional file.
2. The total final enrolment number has been added.
3. The EudraCT number has been added.