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

NCT01617226 | Completed Phase 2 DMC

• 1 other identifier: RG_11-187
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 13

Brief 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.

Conditions

Leukemia, Myeloid, Acute

Outcome Measures

Primary Outcomes (2)

• 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.

  Upto 6 months

• 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.

  Up to 24 months

Secondary Outcomes (6)

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

  Up to 28 days

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

  Up to 6 months

• Phase II - Duration of response

  Up to 24 months

• Phase II - Dose intensity

  Up to 24 months

• Phase II - Quality of Life measured by questionnaires

  Up to 24 months

Study Arms (2)

azacitidine

ACTIVE COMPARATOR

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 and vorinostat

ACTIVE COMPARATOR

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; Drug: Vorinostat

Interventions

Azacitidine DRUG

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

Also known as: vidaza, ATC code L01BC07, cas number 320-67-2

azacitidine; azacitidine and vorinostat

Vorinostat DRUG

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.

Also known as: MK-0683, ATC code L01XX38, cas number 149647-78-9

azacitidine and vorinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Birmingham: lead
• Leukemia Research Fund: collaborator
• Celgene: collaborator
• Merck Sharp & Dohme LLC: collaborator

Study Sites (13)

Barts and the London NHS Trust

London, Greater London, E1 1BB, United Kingdom

Location

King's College Hospital

London, Greater London, SE5 9RS, United Kingdom

Location

Hammersmith Hospital

London, Greater London, W12 0HS, United Kingdom

Location

The Christie Hospital

Manchester, Greater Manchester, M20 4BX, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, Merseyside, L7 8XP, United Kingdom

Location

Belfast City Hospital

Belfast, Northern Ireland, BT9 7AD, United Kingdom

Location

Nottingham University Hospitals NHS Trust

Nottingham, Nottinghamshire, NG27 2UH, United Kingdom

Location

Oxford University Hospitals NHS Trust

Oxford, Oxfordshire, OX3 9DU, United Kingdom

Location

University Hospital of Wales

Cardiff, South Wales, CF14 4XW, United Kingdom

Location

Queen Elizabeth Hospital

Birmingham, West Midlands, B152TH, United Kingdom

Location

St James's University Hospital

Leeds, West Yorkshire, LS9 7TF, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, G12 0YN, United Kingdom

Location

Southampton General Hospital

Southampton, SO16 6YD, United Kingdom

Location

Related Publications (16)

• 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.

  PMID: 14673054 BACKGROUND

• 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.

  PMID: 19880497 BACKGROUND

• 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.

  PMID: 20026804 BACKGROUND

• 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.

  PMID: 16967444 BACKGROUND

• 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.

  PMID: 17596541 BACKGROUND

• 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.

  PMID: 19235255 BACKGROUND

• 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.

  PMID: 20672358 BACKGROUND

• 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.

  PMID: 17962510 BACKGROUND

• 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.

  PMID: 19036090 BACKGROUND

• 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.

  PMID: 10694544 BACKGROUND

• 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.

  PMID: 19357394 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Azacitidine; Vorinostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Study Officials

• Charles F Craddock, Professor

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Haemato-Oncology, Director of Stem Cell Transplant Unit and Transitional Director of Birmingham Health Partners

Study Record Dates

• First Submitted: June 6, 2012
• First Posted: June 12, 2012
• Study Start: September 1, 2012
• Primary Completion: March 1, 2016
• Study Completion: December 1, 2020
• Last Updated: May 5, 2021

Record last verified: 2021-04

Locations

GB (13)