Randomised Study of Azacitidine Versus Azacitidine in Combination With Vorinostat in Patients With Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes (RAvVA)
This is a multicentre, open-label, randomised phase II trial comparing azacitidine monotherapy with combined azacitidine and vorinostat in patients with newly diagnosed, relapsed or refractory acute myeloid leukaemia or high risk myelodysplastic syndromes ineligible for intensive chemotherapy.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Randomised Trial of 5-azacitidine Versus 5-azacitidine in Combination With Vorinostat in Patients With Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes Ineligible for Intensive Chemotherapy|
- Phase II - Overall Response Rate [ Time Frame: Upto 6 months ] [ Designated as safety issue: No ]Patients are expected to receive 6 cycles of treatment which is expected to be completed over a period of 6 months. Each cycle lasts for 28 days. Overall response rate (CR, CRi, PR) as defined by Cheson criteria will be assessed during this time. This will be measured for all patients receiving treatment recruited over a 24 month period.
- Phase II - Overall Survival [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]Overall survival is defined as the time from date of randomisation to the date of death from any cause. Patients discontinuing study, lost to follow up or still alive at the end of the study (up to 24 months) will be censored at the date of last follow-up.
- Phase II - Toxicities measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]Toxicities will be measured and graded according to the NCI CTCAE v4 from the date of randomisation until 28 days following treatment discontinuation over the duration of the follow up period which is 24 months.
- Phase II - Complete Remission (CR) within 6 cycles of treatment [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]Complete remission within 6 cycles of treatment as defined by Cheson criteria will be assessed. It is expected patients will receive 6 cycles of treatment, which is expected to be completed over a period of 6 months, as each cycle is 28 days. This will be measured for all patients receiving treatment recruited over a 24 month period.
- Phase II - Duration of response [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]This will be measured from date of documented response until date of documented progression, assessed for up to 24 months.
- Phase II - Dose intensity [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]Dose intensity defined as the total dose prescribed to each patient as a proportion of the protocol dose. This will measured for each patient receiving treatment, assessed up to 24 months.
- Phase II - Quality of Life measured by questionnaires [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]Quality of Life will be measured using the EORTC QLQ-C30 and EuroQol EQ-5D-5L questionnaires. This will be measured for each patient receiving treatment until end of treatment, assessed for up to 24 months.
- Phase II - Medical Resource Use [ Time Frame: Up to 24 months ] [ Designated as safety issue: No ]Medical resource use is defined in terms of days in hospital, blood product usage and days on anti-biotics and will be measured from date of randomisation until 24 months.
|Study Start Date:||September 2012|
|Estimated Study Completion Date:||September 2016|
|Estimated Primary Completion Date:||September 2013 (Final data collection date for primary outcome measure)|
|Active Comparator: azacitidine||
Azacitidine both arms; 75mg/m^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.
Other Name: vidaza, ATC code L01BC07, cas number 320-67-2
|Active Comparator: azacitidine and vorinostat||
Vorinostat (with azacitidine) combined therapy arm; 300mg twice daily for 7 days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles.
Other Name: MK-0683, ATC code L01XX38, cas number 149647-78-9
Acute Myeloid Leukaemia (AML) is a common haematological malignancy. As a result of improvements in myelosuppressive chemotherapy and stem cell transplantation, the outcome of children and young adults with AML has improved substantially in the past three decades. By contrast there has only been limited progress in the development of new treatments for older adults in whom long term survival is less than 20% at present.
There is an urgent need to develop more effective treatment options for the treatment of AML and high risk MDS in older adults. Accumulating evidence suggests that Azacitidine is a potentially important treatment modality in newly diagnosed, relapsed/refractory AML and high risk MDS. Phase II trials in AML and MDS demonstrate increased clinical activity of azacitidine when combined with a HDACi. However no randomised trials have yet examined the important question of whether concurrent HDACi administration increases the clinical activity of Azacitidine. Vorinostat is a new HDACi which shows significant clinical activity in combination with Azacitidine in patients with AML and MDS.
We therefore propose a randomised trial of azacitidine compared with azacitidine and vorinostat combination therapy in older adults with newly diagnosed, relapsed, refractory AML or high risk MDS ineligible for intensive chemotherapy. This will represent the first randomised trial, addressing whether there is a clinical benefit to be gained from combining treatment with azacitidine with a HDACi in patients with newly diagnosed, relapsed, refractory AML or high risk MDS for whom limited therapeutic options currently exist.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01617226
|Contact: Charles F Craddock, MD||(+44) 0121 371 firstname.lastname@example.org|
|Contact: Nadira Y Jilani, MSc, BSc||(+44) 0121 371 email@example.com|
|Barts and the London NHS Trust||Recruiting|
|London, Greater London, United Kingdom, E1 1BB|
|Principal Investigator: Jamie Cavenagh, FRCPath|
|Hammersmith Hospital||Not yet recruiting|
|London, Greater London, United Kingdom, W12 0HS|
|Principal Investigator: Jiri Pavlu, MD|
|King's College Hospital||Not yet recruiting|
|London, Greater London, United Kingdom, SE5 9RS|
|Principal Investigator: Ghulam Mufti, FRCP, MBBS|
|The Christie Hospital||Recruiting|
|Manchester, Greater Manchester, United Kingdom, M20 4BX|
|Principal Investigator: Mike Dennis, CCST, MD|
|Royal Liverpool University Hospital||Recruiting|
|Liverpool, Merseyside, United Kingdom, L7 8XP|
|Principal Investigator: Richard Clark, FRCPath|
|Belfast City Hospital||Not yet recruiting|
|Belfast, Northern Ireland, United Kingdom, BT9 7AD|
|Principal Investigator: Mary McMullin, PGCHET|
|Nottingham University Hospitals NHS Trust||Recruiting|
|Nottingham, Nottinghamshire, United Kingdom, NG27 2UH|
|Principal Investigator: Nigel Russell, FRCPath|
|Oxford University Hospitals NHS Trust||Recruiting|
|Oxford, Oxfordshire, United Kingdom, OX3 9DU|
|Principal Investigator: Paresh Vyas, FRCPath|
|University Hospital of Wales||Recruiting|
|Cardiff, South Wales, United Kingdom, CF14 4XW|
|Principal Investigator: Steven Knapper, DM Oxon, CST|
|Queen Elizabeth Hospital||Recruiting|
|Birmingham, West Midlands, United Kingdom, B152TH|
|Principal Investigator: Charles Craddock, MRCPath|
|St James's University Hospital||Recruiting|
|Leeds, West Yorkshire, United Kingdom, LS9 7TF|
|Principal Investigator: David Bowen, MCRPath|
|Beatson West of Scotland Cancer Centre||Recruiting|
|Glasgow, United Kingdom, G12 0YN|
|Principal Investigator: Mhairi Copland, MRCP, PhD|
|Southampton General Hospital||Recruiting|
|Southampton, United Kingdom, SO16 6YD|
|Principal Investigator: Srinivasan Narayanan, FRCPath|
|Principal Investigator:||Charles F Craddock, Professor||University of Birmingham|