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 |
| Clinical Trials Information System (CTIS) | 2005-004454-27 |
| Protocol serial number | AZAVATRA _V01 |
| Sponsor | Heinrich-Heine-University (Germany) |
| Funder | Heinrich-Heine-University (Germany) |
- 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
Scientific
Department of Haematology, Oncology and Clinical Immunology
Moorenstrasse 5
Duesseldorf
40225
Germany
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Phase II, open, prospective, single-armed, multicentre trial. |
| Secondary study design | Multi-centre |
| 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 |
| 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(s) |
Safety/toxicity, assessed at one year after treatment start. |
| Key secondary outcome measure(s) |
All endpoints will be assessed at one year after treatment start: |
| Completion date | 01/05/2010 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Not Specified |
| Sex | Not Specified |
| Target sample size at registration | 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
40225
Germany
Results and Publications
| Individual participant data (IPD) Intention to share | No |
|---|---|
| IPD sharing plan summary | 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.
