Condition category
Cancer
Date applied
28/03/2007
Date assigned
19/07/2007
Last edited
19/07/2007
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Prof Norbert Gattermann

ORCID ID

Contact details

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

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

AZAVATRA _V01

Study information

Scientific title

Acronym

AZAVATRA

Study hypothesis

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

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).

Study design

Phase II, open, prospective, single-armed, multicentre trial.

Primary study design

Interventional

Secondary study design

Multi-centre

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Condition

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

Phase

Phase II

Drug names

5-Azacytidine (5-Aza), Valproic Acid (VPA), and All-Trans Retinoic Acid (ATRA)

Primary outcome measures

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 trial start date

19/03/2007

Overall trial end date

01/05/2010

Reason abandoned

Eligibility

Participant 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

Participant type

Patient

Age group

Not Specified

Gender

Not Specified

Target number of participants

25

Participant exclusion criteria

1. Impaired liver or kidney function
2. Pregnancy
3. Simultaneous participation in another clinical trial

Recruitment start date

19/03/2007

Recruitment end date

01/05/2010

Locations

Countries of recruitment

Germany

Trial participating centre

Department of Haematology, Oncology and Clinical Immunology
Duesseldorf
40225
Germany

Sponsor information

Organisation

Heinrich-Heine-University (Germany)

Sponsor details

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

Sponsor type

University/education

Website

http://www.uni-duesseldorf.de/

Funders

Funder type

University/education

Funder name

Heinrich-Heine-University (Germany)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes