Randomised Study of Azacitidine Versus Azacitidine in Combination With Vorinostat in Patients With Acute Myeloid Leukaemia or High Risk Myelodysplastic Syndromes (RAvVA)

This study is currently recruiting participants.
Verified July 2013 by University of Birmingham
Sponsor:
Collaborators:
Leukemia Research Fund
Celgene Corporation
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Professor Charles Craddock, University of Birmingham
ClinicalTrials.gov Identifier:
NCT01617226
First received: June 6, 2012
Last updated: July 16, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Leukemia, Myeloid, Acute
Drug: Azacitidine
Drug: Vorinostat
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by University of Birmingham:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 160
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)
Arms Assigned Interventions
Active Comparator: azacitidine Drug: 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 Drug: 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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Adults with AML (except Acute Promyelocytic Leukaemia (APL)) as defined by the World Health Organisation (WHO) Classification or patients with high risk MDS categorised as INT-2 or high risk according to the International Prognostic Scoring System (IPSS) who are deemed ineligible for intensive chemotherapy on the grounds of age or co-morbidities with ONE of the following disease status:- i) Newly diagnosed OR

ii) Relapsed Disease: patients must have achieved a previous morphological CR and show evidence of recurrent disease OR

iii) Refractory Disease: patients who have failed to achieve a morphological CR with previous therapy

  • Patients are able to receive treatment as out-patient
  • Adequate renal and hepatic function as defined in the Protocol
  • Patients have given written informed consent
  • ECOG performance status less than or equal to 2

Exclusion Criteria:

  • Patients with greater than class III NYHA cardiac impairment
  • Blastic transformation of Chronic Myeloid Leukaemia
  • Prior allogeneic/autologous haematopoietic stem cell transplant
  • Pregnant or lactating women
  • Adults of reproductive potential not willing to use appropriate, effective, contraception during the trial and for specified amount of time afterwards
  • Patients who have received prior histone deacetylase inhibitor (HDACi) treatment as anti-tumour therapy. (Patients who have received HDACi treatment for other indications e.g valproic acid for epilepsy may enrol after a 30-day washout period)
  • Previous anti-tumour therapies, including prior experimental agents or approved anti-tumour small molecules and biologics, within 30 days before the start of protocol treatment. (Patients receiving anti-tumour therapies to control blood counts may enrol into the trial)
  • Patients who have received prior treatment with demethylating agents such as 5-azacitidine or decitabine
  • Patients with contraindications to receiving azacitidine or vorinostat such as hypersensitivity, patients unable to have a subcutaneous injection or swallow oral capsules
  • Active symptomatic fungal, bacterial, and/or viral infection including known active HIV or known viral (A, B, or C) hepatitis
  • Any co-morbidity that could limit compliance with the trial
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01617226

Contacts
Contact: Charles F Craddock, MD (+44) 0121 371 4365 charles.craddock@uhb.nhs.uk
Contact: Nadira Y Jilani, MSc, BSc (+44) 0121 371 4365 n.y.jilani@bham.ac.uk

Locations
United Kingdom
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         
Sponsors and Collaborators
University of Birmingham
Leukemia Research Fund
Celgene Corporation
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Charles F Craddock, Professor University of Birmingham
  More Information

Publications:
Garcia-Manero G, Estey EH, Jabbour E, et al. Phase II Study of 5-Azacitidine and Vorinostat in Patients (pts) with Newly Diagnosed Myelodysplastic Syndrome (MDS) or Acute Myelogenous Leukaemia (AML) not eligible for Clinical Trials because of poor performance or presence of other comorbidities. Blood (ASH annual meeting abstracts) 116: Abstract 604, 21010.
Guieze R, Jouinot A, Itzykson R, et al. Azacytidine (AZA) in Relapsed MDS and AML after allogeneic stem cell transplantation (allo-HSCT): Results of the French ATU Program. Blood (ASH Annual Meeting Abstracts), Abstract 1293, 2010.
Craddock CF, Goardon N, Quek L. et al. 5'azacitidine in combination with valproic acid induces complete remissions in patients with advanced acute myeloid leukaemia but does not eradicate clonal leukaemic progenitors. Blood (ASH annual meeting abstracts), Abstract 638, 2011.
Silverman LR, Verma A, Odchimar-Reissig R et al. A Phase I Trial of the Epigenetic Modulators Vorinostat, in combination with Azacitidine (azaC) in Patients with the Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukaemia (AML): A Study of the New York Cancer Consortium. Blood (ASH Annual Meeting Abstracts), 112: Abstract 3656, 2008.

Responsible Party: Professor Charles Craddock, Professor of Haemato-Oncology, Director of Stem Cell Transplant Unit and Transitional Director of Birmingham Health Partners, University of Birmingham
ClinicalTrials.gov Identifier: NCT01617226     History of Changes
Other Study ID Numbers: RG_11-187
Study First Received: June 6, 2012
Last Updated: July 16, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Vorinostat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on April 15, 2014