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 designPhase II, open, prospective, single-armed, multicentre trial.
Primary study designInterventional
Secondary study designMulti-centre
Study setting(s)Hospital
Study typeTreatment
Scientific titlePhase 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 acronymAZAVATRA
Study objectivesMyelodysplastic 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) studiedMyelodysplastic syndromes (MDS)
InterventionEpigenetic 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 typeDrug
Pharmaceutical study type(s)
PhasePhase II
Drug / device / biological / vaccine name(s)5-Azacytidine (5-Aza), Valproic Acid (VPA), and All-Trans Retinoic Acid (ATRA)
Primary outcome measureSafety/toxicity, assessed at one year after treatment start.
Secondary outcome measuresAll endpoints will be assessed at one year after treatment start:
1. Haematological response
2. Progression-free survival
3. Overall survival
Overall study start date19/03/2007
Completion date01/05/2010

Eligibility

Participant type(s)Patient
Age groupNot Specified
SexNot Specified
Target number of participants25
Total final enrolment24
Key inclusion criteria1. 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 criteria1. Impaired liver or kidney function
2. Pregnancy
3. Simultaneous participation in another clinical trial
Date of first enrolment19/03/2007
Date of final enrolment01/05/2010

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 logo "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 shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing planNot 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.