Randomised Study of Azacitidine Versus Azacitidine With Vorinostat in Patients With AML or High Risk MDS
NCT ID: NCT01617226
Last Updated: 2021-05-05
Study Results
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Basic Information
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COMPLETED
PHASE2
260 participants
INTERVENTIONAL
2012-09-30
2020-12-31
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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
Azacitidine
Azacitidine both arms; 75mg/m\^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.
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).
Azacitidine
Azacitidine both arms; 75mg/m\^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.
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.
Interventions
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Azacitidine
Azacitidine both arms; 75mg/m\^2 by subcutaneous injection for 7 days of a 28-day cycle for up to 6 cycles.
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
* 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
18 Years
ALL
No
Sponsors
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Leukemia Research Fund
OTHER
Celgene
INDUSTRY
Merck Sharp & Dohme LLC
INDUSTRY
University of Birmingham
OTHER
Responsible Party
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Professor Charles Craddock
Professor of Haemato-Oncology, Director of Stem Cell Transplant Unit and Transitional Director of Birmingham Health Partners
Principal Investigators
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Charles F Craddock, Professor
Role: PRINCIPAL_INVESTIGATOR
University of Birmingham
Locations
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Barts and the London NHS Trust
London, Greater London, United Kingdom
King's College Hospital
London, Greater London, United Kingdom
Hammersmith Hospital
London, Greater London, United Kingdom
The Christie Hospital
Manchester, Greater Manchester, United Kingdom
Royal Liverpool University Hospital
Liverpool, Merseyside, United Kingdom
Belfast City Hospital
Belfast, Northern Ireland, United Kingdom
Nottingham University Hospitals NHS Trust
Nottingham, Nottinghamshire, United Kingdom
Oxford University Hospitals NHS Trust
Oxford, Oxfordshire, United Kingdom
University Hospital of Wales
Cardiff, South Wales, United Kingdom
Queen Elizabeth Hospital
Birmingham, West Midlands, United Kingdom
St James's University Hospital
Leeds, West Yorkshire, United Kingdom
Beatson West of Scotland Cancer Centre
Glasgow, , United Kingdom
Southampton General Hospital
Southampton, , United Kingdom
Countries
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References
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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.
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.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Other Identifiers
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RG_11-187
Identifier Type: -
Identifier Source: org_study_id
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