Randomised Study of Azacitidine Versus Azacitidine With Vorinostat in Patients With AML or High Risk MDS (RAvVA)

April 30, 2021 updated by: Professor Charles Craddock, University of Birmingham

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

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

260

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • Glasgow, United Kingdom, G12 0YN
        • Beatson West of Scotland Cancer Centre
      • Southampton, United Kingdom, SO16 6YD
        • Southampton General Hospital
    • Greater London
      • London, Greater London, United Kingdom, E1 1BB
        • Barts and the London NHS Trust
      • London, Greater London, United Kingdom, SE5 9RS
        • King's College Hospital
      • London, Greater London, United Kingdom, W12 0HS
        • Hammersmith Hospital
    • Greater Manchester
      • Manchester, Greater Manchester, United Kingdom, M20 4BX
        • The Christie Hospital
    • Merseyside
      • Liverpool, Merseyside, United Kingdom, L7 8XP
        • Royal Liverpool University Hospital
    • Northern Ireland
      • Belfast, Northern Ireland, United Kingdom, BT9 7AD
        • Belfast City Hospital
    • Nottinghamshire
      • Nottingham, Nottinghamshire, United Kingdom, NG27 2UH
        • Nottingham University Hospitals NHS Trust
    • Oxfordshire
      • Oxford, Oxfordshire, United Kingdom, OX3 9DU
        • Oxford University Hospitals NHS Trust
    • South Wales
      • Cardiff, South Wales, United Kingdom, CF14 4XW
        • University Hospital of Wales
    • West Midlands
      • Birmingham, West Midlands, United Kingdom, B152TH
        • Queen Elizabeth Hospital
    • West Yorkshire
      • Leeds, West Yorkshire, United Kingdom, LS9 7TF
        • St James's University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: azacitidine
azacitidine (75mg/m2) by SC injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. This should be delivered in a 5-2-2 schedule
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 Names:
  • vidaza, ATC code L01BC07, cas number 320-67-2
Active Comparator: azacitidine and vorinostat
Patients will receive (75mg/m2) azacitidine by SC injection on 7 consecutive days (excluding weekends), starting day 1 of 28-day cycles for up to 6 cycles. Azacitidine should be delivered in a 5-2-2 schedule. Vorinostat (300mg bid) will be taken orally for 7 consecutive days starting on day 3 of each cycle in 28-day cycles for up to 6 cycles. (Day 3 is defined as the 3rd day of azacitidine administration).
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 Names:
  • vidaza, ATC code L01BC07, cas number 320-67-2
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 Names:
  • MK-0683, ATC code L01XX38, cas number 149647-78-9

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase II - Overall Response Rate
Time Frame: Upto 6 months
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.
Upto 6 months
Phase II - Overall Survival
Time Frame: Up to 24 months
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.
Up to 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase II - Toxicities measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)
Time Frame: Up to 28 days
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.
Up to 28 days
Phase II - Complete Remission (CR) within 6 cycles of treatment
Time Frame: Up to 6 months
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.
Up to 6 months
Phase II - Duration of response
Time Frame: Up to 24 months
This will be measured from date of documented response until date of documented progression, assessed for up to 24 months.
Up to 24 months
Phase II - Dose intensity
Time Frame: Up to 24 months
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.
Up to 24 months
Phase II - Quality of Life measured by questionnaires
Time Frame: Up to 24 months
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.
Up to 24 months
Phase II - Medical Resource Use
Time Frame: Up to 24 months
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.
Up to 24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Birmingham

Collaborators

Merck Sharp & Dohme LLC
Celgene
Leukemia Research Fund

Investigators

  • Principal Investigator: Charles F Craddock, Professor, University of Birmingham

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2012

Primary Completion (Actual)

March 1, 2016

Study Completion (Actual)

December 1, 2020

Study Registration Dates

First Submitted

June 6, 2012

First Submitted That Met QC Criteria

June 7, 2012

First Posted (Estimate)

June 12, 2012

Study Record Updates

Last Update Posted (Actual)

May 5, 2021

Last Update Submitted That Met QC Criteria

April 30, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RG_11-187

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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