RAvVA
Research type
Research Study
Full title
Phase I/II Randomised Trial of 5-Azacitidine versus 5-Azacitidine in combination with Vorinostat in patients with Relapsed Acute Myeloid Leukaemia ineligible for Intensive Chemotherapy
IRAS ID
92659
Contact name
Charles Craddock
Eudract number
2011-005207-32
Clinicaltrials.gov Identifier
N/A
Research summary
Summary of Research
This is a multicentre, open-label trial, rolling from a phase I dose-finding study into a randomised phase II trial comparing azacitidine monotherapy with combined azacitidine and vorinostat in patients with relapsed acute myeloid leukaemia (AML) ineligible for intensive chemotherapy. The trial will consist of two parts, a phase I component to determine the maximum tolerated dose (MTD) of the combined therapy arm, and a subsequent randomised phase II trial. Initially a Phase I component to the trial will be performed to determine the MTD to be administered in the combined therapy arm of azacitidine and vorinostat. A standard dose escalation (cumulative 3 design) will be used to evaluate two doses (cohort 1 = azacitidine 55mg/m2 vorinostat 200mg bid and cohort 2 = azacitidine 55mg/m2 vorinostat 300mg bid). The MTD will be taken forward into the phase II component of the trial. In the Phase II part, patients with relapsed AML, deemed ineligible for intensive chemotherapy, will be randomised on a 1:1 ratio to treatment with monthly cycles of azacitidine monotherapy or combined azacitidine and vorinostat. The dose of the combined therapy will be determined from the Phase I component of this study. Patients will be assessed for Overall Response as defined by the Cheson criteria after cycles 3 and 6.Summary of Results
Trial nameRAvVA - Phase II Randomised Trial of 5-Azacitidine versus 5-Azacitidine in combination with Vorinostat in patients with Acute Myeloid Leukaemia (AML) or High Risk Myelodysplastic Syndromes (MDS) Ineligible for Intensive Chemotherapy Protocol number: RG_11-187 EU Trial number: 2011-005207-32
Abstract
Purpose of the study: To see if a combination of azacitidine and vorinostat is better than azacitidine alone, for people who can’t have intensive chemotherapy or a stem cell transplant for AML or MDS.What was tested: Azacitidine alone was compared to azacitidine plus vorinostat in a phase 2 trial. In a phase 2 study, a comparison can be made with a smaller number of patients to see if it’s worthwhile doing a larger trial.
People taking part: 259 adults with AML or MDS in the United Kingdom took part and were recruited over approximately 3 years.
Results: The combination of azacitidine and vorinostat was not superior to azacitidine alone in terms of length of survival or improvement of disease.
Safety: In this study, researchers found that the level of side effects was similar for both treatment groups.
Who sponsored this study?
This study was sponsored by the University of Birmingham. The RAvVA trials office can be contacted via RAvVA@trials.bham.ac.uk.General Information about the trial
The study took place in the United Kingdom only. Recruitment began in September 2012 and ended in September 2015. The trial closed in December 2020 when all patients had stopped trial treatment and all data had been collected.
The main objective of the study was to test if the combination of azacitidine and vorinostat was better than azacitidine alone in terms of survival and disease improvement, for people who could not have intensive chemotherapy for their AML or MDS. Azacitidine alone had already been found to be beneficial to patients with these cancers and it was thought adding vorinostat would improve disease responses and survival times in this area of clinical unmet need. Some early phase trials had already shown this might be a useful combination.
The trial was changed part way through to recruit an additional 100 patients (original target 160) and to include patients with AML and MDS who were at different stages of their disease and treatment, rather than just patients whose disease had come back for the first time.What patients were included in this study?
This trial included patients with AML and high risk MDS who were ineligible for intensive chemotherapy or stem cell transplant. Patients could be newly diagnosed, have relapsed disease (their cancer had returned) or have refractory disease (previous treatment had not worked).
Although the trial was open to all adults, the vast majority of patients in this study were elderly with 87% being 65 years and over. Slightly more men than women took part (60% compared to 40%).Patients needed to have adequate liver and kidney function to participate and be fit and able to attend hospital to receive treatment as an out-patient. They also needed to be able to provide informed consent to participate.
Patients were not able to participate in the trial if they had significant heart disease, had previously received a stem cell transplant, were at an advanced stage of chronic myeloid leukaemia or had active symptoms of a fungal, viral or bacterial infection.
Patients also could not have received any prior treatment with azacitidine or vorinostat or very similar drugs. Patients needed to agree to use effective contraception during the trial and could not be pregnant or lactating at trial entry.Which medicines were studied?
Patients were randomly allocated into equal groups to receive azacitidine alone or azacitidine with vorinostat. Azacitidine is a type of drug called a hypomethylating agent. It works by switching off a protein called DNA methyltransferase. This switches on genes that stop the cancer cells growing and dividing. This reduces the number of abnormal blood cells and helps to control cell growth. Vorinostat is a type of targeted cancer drug called a cancer growth blocker. It stops signals that cancer cells use to divide and grow.
What were the side effects?
Serious Adverse Events (SAEs) were reported whilst patients were on trial treatment and for 4 weeks after they finished treatment. SAEs include untoward medical occurrences that result in patients being admitted to hospital, are life threatening, result in death, cause long term or significant disability or incapacity or cause birth defects.
Hospitalisations for supportive treatment due to the patient’s cancer getting worse or death from their AML or MDS were not reported as SAEs. Unfortunately this was expected for this patient group and would not be considered related to trial treatment.
461 SAEs were reported of which 349 were considered related to trial therapy. In this high risk patient population the great majority of individual SAEs occurred in fewer than 2% of the trial population, and therefore have not been included in this summary. 25 SAEs resulted in death, 15 of these were felt to be at least possibly related to trial treatment.
The most common serious side effect of this study was febrile neutropenia (experiencing a fever when the number of white blood cells, specifically neutrophils, are very low) which is a common presenting feature of untreated AML or MDS and a frequent occurrence and potentially life-threatening complication in patients treated with standard chemotherapy. 31.3% of patients experienced febrile neutropenia and 139/145 occurrences were considered related to trial treatment, including 3 treatment related deaths. The incidence of febrile neutropenia was similar for both treatment groups (30.3% vs 32%) The next most common SAEs (percentage patients affected overall) were sepsis (20.5%), infections (15.4%), fever (10.2%), diarrhoea (4.9%), constipation (4.1%), vomiting (4.1%), chest pain (2.5%), nausea (2.1%), dyspnoea – shortness of breath (2%) and epistaxis - nose bleed (2%).
The trial also collected Adverse Events (AEs) where they were Grade 3 or above. These are medical occurrences that are considered severe or medically significant but not immediately life threatening. These AEs include events both related and unrelated to trial treatment.
975 AEs (495 in the azacitidine group and 480 in the azacitidine and vorinostat group) were experienced by 152 patients (71 in the azacitidine arm and 81 in the azacitidine and vorinostat group). The following AEs were experienced by at least 5% of patients overall across both groups; platelet count decreased (26.9%), neutrophil count decreased (22.3%), anaemia (17.8%), white blood cell decreased (14.5%), febrile neutropenia (11.6%) and sepsis (5.4%). All of these events relate to fewer functioning blood cells being produced by the bone marrow which is both a side effect of chemotherapy treatments and something that is commonly observed in patients with AML and MDS.
What were the overall results of the study?
It was concluded that the combination of azacitidine and vorinostat was not better than azacitidine alone for AML and high risk MDS.
The research team looked at how many people’s AML or MDS improved with treatment. It was nearly the same in both groups at just over 4 out of 10 or 42% overall (41% in the acacitidine group and 42% in the azacitidine and vorinostat group). Of the patients who did see an improvement, this lasted on average 10.6 months for the patients receiving azacitidine alone and 11.3 months for patients receiving azacitidine with vorinostat.
24% of patients across the trial achieved a complete response (where no cancer was found in their bone marrow). Again this was similar for both groups with 22% of patients who received azacitidine and 26% of patients who received the combination.
They also looked at how long people lived for, and found it was similar in the two groups: 9.8 months for those who azacitidine and 11.1 months for those had has azacitidine and vorinostat.
Nearly all patients received the full doses of trial treatment they were prescribed.
The study also aimed to see if there was a difference in the supportive care requirements of patients between the groups receiving trial treatment. The study looked at days in hospital, the need for blood products (transfusions) and the need for anti-infection medication.
If we do not include the SAE hospitalisations mentioned above, the median (middle number) of days patients spent in hospital was 15 for patients who received azacitidine alone and 9 for patients who received azacitidine and vorinostat.
The need for blood product transfusions were similar across the groups.
The median number of days that patients on the azacitidine arm received antibacterial, anti-fungal and anti-viral medications was 53, 79 and 111 respectively. This compares to 64, 121 and 183 for patients who received the combination.
The study also collected information on patient’s quality of life by asking patients to complete questionnaires throughout their time on the trial. Again the results were very similar for both treatment groups.
In addition, laboratory researchers looked at cells from samples of bone marrow from the people taking part. They looked for specific changes (mutations) in genes in the cells that may help them predict how well treatment will work. They found that if the cells had certain genetic changes, then treatment was less likely to work. The changes were in genes called CDKN2A, TP53 and IDH1.How has this study helped patients and researchers?
Recent studies have shown that the combination of azacitidine and vorinostat does not improve disease or survival in patients with MDS but this study was the first to demonstrate this in AML. This is an important observation since it does not support further examination of an azacitidine/ vorinostat combination in AML. The laboratory research performed in this study has fundamentally advanced the understanding of how azacitidine, which is still an extremely important anti-leukaemic drug, works and this may help identify better partner treatments in future.It is important to note that this outcome reflects this specific trial and other trials may show something different.The final analysis for this study was completed in December 2021.
Are there plans for further studies?
Azacitidine is now available in many countries, including in the UK via the NHS, for the treatment of intermediate-2 and high-risk myelodysplastic syndromes, chronic myelomonocytic leukaemia, and acute myeloid leukaemia, in adults who are not eligible for haemotopoietic stem cell transplantation. The combination with vorinostat has not been taken forward.Where can I find more information about this study?
To learn about this study, you can find more detailed information on the EU database.https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agba4yu73OCS9U-2BkKS40W1kfatiYvtk1-2B2gi1K6vKImual-2B6BVK7DtVHgC38pGjLOkQQ-3D-3D5v6Z_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YKUV6FKsoMX39sPfB7Dzro2ayKrT3hQoghP0hbH7vzKq9srK4Xqu09THKSKWyMWYBqRAxKQ1qhqEug-2BnKCgm0LGV51pERSCszgDLnJC2sTEbM-2FAkv0fzfddSJbPDk0tfLW309YcWs7dml46w6NVr0oXpm97X5ZAuDKSPoMcrWTIJw-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7C875291ae07a04494e12408d9c3eda4e9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637756247701708133%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=b6pbt9%2BcU8JBT83cZ%2F23bR716dvi7l%2Bb0RHOBNB7ZhU%3D&reserved=0
A summary is also provided on the Cancer Research UK website.
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Furl6570.hra.nhs.uk%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbZ0oYz60WoglvPkqIfU1HPHTUfauCq2ZPvNtWjz0kGXSOCiSOfyPyipJY7AGHLby83CxCKkzl39Br4eiOAMc6C5H6sgjkmCCTIZHPSP7fpZ8apxXZBGvEx8-2BfiUaZRZL57HWMlcW9kyEPF-2FHFmjJH3wF0SmE113CNPXZPptkFavLG8IU0K70VlnPRqHwLOpVOYDNMBDuPdaLaq7O-2BiRijLM-3DE9k3_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YKUV6FKsoMX39sPfB7Dzro2B40BiKrHn-2B4kbk-2FovzdtDza9EQ5B8IdMhqbYaK3CmFpdZejzjxd5NKkG0a1eZjxPMQaaiMtyUgPrepLnhVZlLfhZPI1SCbE-2FoO2jdSnCDxpPh0B5aABnCjvKSnnYQ9v04K3eYPOZnuw2TUGa4BL18Q-3D-3D&data=04%7C01%7Capprovals%40hra.nhs.uk%7C875291ae07a04494e12408d9c3eda4e9%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637756247701708133%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000&sdata=2OCsTDwOEyR3V%2B%2FZoztp35uM8KmSEz9tNBJwWarzNQM%3D&reserved=0
REC name
West Midlands - Edgbaston Research Ethics Committee
REC reference
12/WM/0087
Date of REC Opinion
21 May 2012
REC opinion
Further Information Favourable Opinion