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Leukemia, Myeloid, AcutePhase 2RAvVANCT01617226

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

A Phase 2 study testing Azacitidine and Vorinostat in people with Leukemia, Myeloid, Acute, run by University of Birmingham at 13 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia, Myeloid, Acute
What is being tested?
Azacitidine and Vorinostat
Could I receive a placebo?
No, everyone receives an active treatment
How many people
260 participants
Where
13 sitesUnited Kingdom
Study dates
Sep 2012to Dec 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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)
Show all 11Show fewer
  • 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

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

United Kingdom13 sites

  • Belfast City Hospital

    Belfast, Northern Ireland, BT9 7AD

  • Queen Elizabeth Hospital

    Birmingham, West Midlands, B152TH

  • University Hospital of Wales

    Cardiff, South Wales, CF14 4XW

  • Beatson West of Scotland Cancer Centre

    Glasgow, G12 0YN

  • St James's University Hospital

    Leeds, West Yorkshire, LS9 7TF

  • Royal Liverpool University Hospital

    Liverpool, Merseyside, L7 8XP

  • Barts and the London NHS Trust

    London, Greater London, E1 1BB

  • King's College Hospital

    London, Greater London, SE5 9RS

  • Hammersmith Hospital

    London, Greater London, W12 0HS

  • The Christie Hospital

    Manchester, Greater Manchester, M20 4BX

  • Nottingham University Hospitals NHS Trust

    Nottingham, Nottinghamshire, NG27 2UH

  • Oxford University Hospitals NHS Trust

    Oxford, Oxfordshire, OX3 9DU

  • Southampton General Hospital

    Southampton, SO16 6YD

Other trials in United Kingdom

About this study

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

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.

Read the 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.

Being tested
Azacitidine, Vorinostat
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AzacitidineDrug

    Also called vidaza, ATC code L01BC07, cas number 320-67-2

    Azacitidine both arms; 75mg/m^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.

  • VorinostatDrug

    Also called MK-0683, ATC code L01XX38, cas number 149647-78-9

    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.

Study groups in NCT01617226
Study groupRoleWhat they receive
azacitidineActive comparatorazacitidine (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
Receives: Drug: Azacitidine
azacitidine and vorinostatActive comparatorPatients 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).
Receives: Drug: Azacitidine; Drug: Vorinostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Phase II - Overall Response Rate

    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.

    Measured: Upto 6 months

  2. Phase II - Overall Survival

    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.

    Measured: Up to 24 months

Secondary outcomes (6)

  1. Phase II - Toxicities measured by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)

    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.

    Measured: Up to 28 days

  2. Phase II - Complete Remission (CR) within 6 cycles of treatment

    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.

    Measured: Up to 6 months

  3. Phase II - Duration of response

    This will be measured from date of documented response until date of documented progression, assessed for up to 24 months.

    Measured: Up to 24 months

  4. Phase II - Dose intensity

    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.

    Measured: Up to 24 months

  5. Phase II - Quality of Life measured by questionnaires

    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.

    Measured: Up to 24 months

  6. Phase II - Medical Resource Use

    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.

    Measured: Up to 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jun 2012 (estimated)
  2. Study startSep 2012
  3. Primary completionMar 2016
  4. Study completionDec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
260 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01617226
Sponsor's protocol ID
RG_11-187
Acronym
RAvVA
Status last verified
Apr 2021
First submitted
6 Jun 2012
Last updated
5 May 2021
Results posted
No
Data monitoring committee
Yes

Publications

  • Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 15;21(24):4642-9. doi: 10.1200/JCO.2003.04.036.

    PubMed 14673054

  • Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Lowenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74. doi: 10.1182/blood-2009-07-235358. Epub 2009 Oct 30.

    PubMed 19880497

  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. doi: 10.1200/JCO.2009.23.8329. Epub 2009 Dec 21.

    PubMed 20026804

  • Sudan N, Rossetti JM, Shadduck RK, Latsko J, Lech JA, Kaplan RB, Kennedy M, Gryn JF, Faroun Y, Lister J. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006 Oct 15;107(8):1839-43. doi: 10.1002/cncr.22204.

    PubMed 16967444

  • Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, Cortes J, Wierda WG, Ouzounian S, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Garcia-Manero G. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007 Oct 1;110(7):2302-8. doi: 10.1182/blood-2007-03-078576. Epub 2007 Jun 27.

    PubMed 17596541

  • Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P, de Padua L, Shpall EJ, Champlin R, de Lima M. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer. 2009 May 1;115(9):1899-905. doi: 10.1002/cncr.24198.

    PubMed 19235255

  • de Lima M, Giralt S, Thall PF, de Padua Silva L, Jones RB, Komanduri K, Braun TM, Nguyen HQ, Champlin R, Garcia-Manero G. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer. 2010 Dec 1;116(23):5420-31. doi: 10.1002/cncr.25500. Epub 2010 Jul 29.

    PubMed 20672358

  • Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008 Feb 1;111(3):1060-6. doi: 10.1182/blood-2007-06-098061. Epub 2007 Oct 25.

    PubMed 17962510

  • Khanim FL, Bradbury CA, Arrazi J, Hayden RE, Rye A, Basu S, MacWhannell A, Sawers A, Griffiths M, Cook M, Freeman S, Nightingale KP, Grimwade D, Falciani F, Turner BM, Bunce CM, Craddock C. Elevated FOSB-expression; a potential marker of valproate sensitivity in AML. Br J Haematol. 2009 Feb;144(3):332-41. doi: 10.1111/j.1365-2141.2008.07449.x. Epub 2008 Nov 22.

    PubMed 19036090

  • Wijermans P, Lubbert M, Verhoef G, Bosly A, Ravoet C, Andre M, Ferrant A. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000 Mar;18(5):956-62. doi: 10.1200/JCO.2000.18.5.956.

    PubMed 10694544

  • Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51. doi: 10.1182/blood-2009-03-209262. Epub 2009 Apr 8.

    PubMed 19357394

  • 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 C, Goardon N, Griffiths M, 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 stem/progenitor cells. Blood (ASH Annual Meeting Abstracts), 112: Abstract 945, 2008.

  • 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.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Azacitidine and Vorinostat in people with Leukemia, Myeloid, Acute, run by University of Birmingham at 13 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 May 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase II - Overall Response Rate (time frame: Upto 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01617226, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2021.

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