The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)
NCT ID: NCT03562169
Last Updated: 2018-06-19
Study Results
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Basic Information
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RECRUITING
PHASE3
406 participants
INTERVENTIONAL
2017-03-20
2027-03-31
Brief Summary
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Primary Objectives
The primary objectives of this study are to determine:
* The impact on Depth of Response (DoR: less than VGPR versus VGPR or better) when salvage ASCT conditioning is augmented by the addition of a proteasome inhibitor
* The influence of a consolidation and maintenance strategy on the Durability of Response (DuR:PFS)
Secondary objectives
The secondary objectives of this study are to determine:
* Overall survival
* Time to disease progression
* The overall response rate following ixazomib, thalidomide and dexamethasone (ITD) re-induction
* Time to next treatment
* Progression-free survival 2 (PFS2)
* Duration of response
* Minimal Residual Disease (MRD) negative rate post re-induction, post-ASCT and conversion after ITD consolidation
* Engraftment kinetics
* Toxicity and safety
* Quality of life (QoL)
Participant population (refer to protocol section 9 for a full list of eligibility criteria).
* Relapsed MM (with measurable disease by IMWG criteria) previously treated with ASCT
* First progressive disease (PD) at least 12 months since first ASCT, requiring therapy.
* ECOG Performance Status 0-2
* Aged at least 18 years
* Adequate full blood count and renal, hepatobiliary, pulmonary and cardiac function
* Written informed consent
Interventions: All participants will be registered at trial entry and will receive re-induction therapy with 4-6, 28-day cycles of ixazomib, thalidomide and dexamethasone (ITD), in order to reach maximum response. Participants who achieve at least stable disease (SD) will be randomised on a 1:1 basis to receive either conventional ASCT (ASCTCon), using melphalan, or augmented ASCT (ASCTAug), using melphalan with ixazomib. All participants achieving or maintaining a minimal response (MR) or better following trial ASCT will undergo a second randomisation to consolidation and maintenance or no further treatment. Participants randomised to consolidation and maintenance will receive treatment as follows: consolidation with 2 cycles of ITD and maintenance with ixazomib until disease progression.
Number of participants: 406 participants will be registered into the trial to allow 284 participants to be randomised at the first randomisation (R1) and 248 participants to be randomised at the second randomisation (R2).
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Conventional Autologous Stem Cell Transplant (ASCT)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0
Ixazomib, thalidomide, & dexamethasone (ITD) re-induction
4 - 6 ITD 28-day cycles as follows:
* Ixazomib 4mg capsule on days 1, 8 and 15
* Thalidomide 100mg capsule on days 1-28
* Dexamethasone 40mg tablets on days 1, 8, 15 and 22
Conventional autologous stem cell transplant (ASCT-con)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0.
ITD consolidation and ixazomib maintenance vs. No further therapy
Participants will be randomised to either 'no further therapy' or 'ITD consolidation and ixazomib maintenance'. Participants randomised to 'no further treatment' will not receive any further treatment but will be followed up at 8 weeks post randomisation 2 and at 3-monthly clinic visits until disease progression.
Participants randomised to ITD consolidation and ixazomib maintenance will receive:
Two 28-day cycles of ITD consolidation (same doses as in ITD re-induction). This will be followed by ixazomib maintenance as follows: Ixazomib 4mg capsule on days 1, 8 and 15 of each 28-day cycle until disease progression.
Augmented Autologous Stem Cell Transplant (ASCT)
Melphalan 100mg/m2 IV infusion on Day -3 and -2 plus ixazomib 4mg capsules on Day -4 and -1. ASCT will then be given on Day 0.
Ixazomib, thalidomide, & dexamethasone (ITD) re-induction
4 - 6 ITD 28-day cycles as follows:
* Ixazomib 4mg capsule on days 1, 8 and 15
* Thalidomide 100mg capsule on days 1-28
* Dexamethasone 40mg tablets on days 1, 8, 15 and 22
Augmented autologous stem cell transplant (ASCT-aug)
Melphalan 100mg/m2 IV infusion on Day -3 and Day -2 plus ixazomib 4mg capsules on Day -4 and Day -1. ASCT will then be given on Day 0.
ITD consolidation and ixazomib maintenance vs. No further therapy
Participants will be randomised to either 'no further therapy' or 'ITD consolidation and ixazomib maintenance'. Participants randomised to 'no further treatment' will not receive any further treatment but will be followed up at 8 weeks post randomisation 2 and at 3-monthly clinic visits until disease progression.
Participants randomised to ITD consolidation and ixazomib maintenance will receive:
Two 28-day cycles of ITD consolidation (same doses as in ITD re-induction). This will be followed by ixazomib maintenance as follows: Ixazomib 4mg capsule on days 1, 8 and 15 of each 28-day cycle until disease progression.
Interventions
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Ixazomib, thalidomide, & dexamethasone (ITD) re-induction
4 - 6 ITD 28-day cycles as follows:
* Ixazomib 4mg capsule on days 1, 8 and 15
* Thalidomide 100mg capsule on days 1-28
* Dexamethasone 40mg tablets on days 1, 8, 15 and 22
Conventional autologous stem cell transplant (ASCT-con)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0.
Augmented autologous stem cell transplant (ASCT-aug)
Melphalan 100mg/m2 IV infusion on Day -3 and Day -2 plus ixazomib 4mg capsules on Day -4 and Day -1. ASCT will then be given on Day 0.
ITD consolidation and ixazomib maintenance vs. No further therapy
Participants will be randomised to either 'no further therapy' or 'ITD consolidation and ixazomib maintenance'. Participants randomised to 'no further treatment' will not receive any further treatment but will be followed up at 8 weeks post randomisation 2 and at 3-monthly clinic visits until disease progression.
Participants randomised to ITD consolidation and ixazomib maintenance will receive:
Two 28-day cycles of ITD consolidation (same doses as in ITD re-induction). This will be followed by ixazomib maintenance as follows: Ixazomib 4mg capsule on days 1, 8 and 15 of each 28-day cycle until disease progression.
Eligibility Criteria
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Inclusion Criteria
2. First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3).
4. Aged at least 18 years.
5. Participants must have the following blood results within 14 days before registration:
1. Absolute neutrophil count (ANC) ≥1x109/L
2. Platelet count ≥75x109/L. If the participant has ≥50% bone marrow infiltration a platelet count of ≥50x109/L is allowed.
Platelet transfusions are not allowed within 3 days before registration in order to meet these values.
6. Adequate renal function within 14 days before registration:
a. Creatinine clearance ≥30ml/min (calculated according to the Cockcroft-Gault equation or other locally approved formula)
7. Adequate hepatobiliary function within 14 days before registration:
1. Total bilirubin \<2 x upper limit of normal (ULN)
2. ALT \<2 x ULN
8. Adequate pulmonary function within 14 days before registration:
a. Adequate respiratory functional reserve (delineated by KCO/DLCO (carbon monoxide diffusion in the lung) of ≥50%). No evidence of a history of pulmonary disease. If a significant history, then a review by a respiratory medicine physician is required.
9. Adequate cardiac function within 12 weeks before registration
a. Left ventricular ejection fraction (LVEF) ≥40%. Note: repeat confirmation of cardiac function is needed if treatment is given between this assessment and registration.
10. Female participants who:
1. Are not of childbearing potential (Appendix 8), OR
2. If they are of childbearing potential (Appendix 8), agree to practice 2 effective methods of contraception (Appendix 8), at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR
3. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence \[e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.)
Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following:
1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
2. Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) Contraception for female and male participants must be in accordance with (and consent to) the Celgene-approved Thalidomide Pregnancy Prevention Programme.
11. If female and of childbearing potential (see Appendix 8), must have a negative pregnancy test performed by a healthcare professional in accordance with the Celgene Thalidomide Pregnancy Prevention Programme.
12. Patients agree not to receive other clinical trials treatment, including investigational medicinal products (IMPs) not included in this trial, within 30 days of trial registration and throughout the duration of the trial, until disease progression.
13. Able to provide written informed consent.
Exclusion Criteria
2. ≥Grade 2 peripheral neuropathy within 14 days before registration.
3. Known HIV seropositivity.
4. Known resistance, intolerance or sensitivity to any component of the planned therapies.
5. Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's participation in this study.
6. Previous or concurrent malignancies at other sites (excluding completely resected non-melanoma skin cancer or carcinoma in situ of any type, such as cervical cancer).
7. Pregnant, lactating or breast feeding female participants.
8. Failure to have fully recovered (i.e.Grade 1 or less toxicity) from the reversible effects of prior chemotherapy.
9. Major surgery within 14 days before registration.
10. Central nervous system involvement with myeloma.
11. Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration.
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
13. Systemic treatment, within 14 days before the first dose of ixazomib with strong CYP3A inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
14. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing.
15. Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.
16. Participant has current or prior hepatitis B or C infection.
18 Years
ALL
No
Sponsors
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Cancer Research UK
OTHER
Takeda
INDUSTRY
University of Leeds
OTHER
Responsible Party
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Principal Investigators
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Head of Trial Management
Role: STUDY_DIRECTOR
Univeristy of Leeds, CTRU
Locations
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Aberdeen Royal Infirmary
Aberdeen, , United Kingdom
Monklands Hospital
Airdrie, , United Kingdom
University Hospital Ayr
Ayr, , United Kingdom
Barnsley Hospital
Barnsley, , United Kingdom
Basingstoke & North Hampshire Hospital
Basingstoke, , United Kingdom
Royal United Hospital
Bath, , United Kingdom
Good Hope Hospital
Birmingham, , United Kingdom
Heartlands Hospital
Birmingham, , United Kingdom
Queen Elizabeth Hospital
Birmingham, , United Kingdom
Blackpool Victoria Hospital
Blackpool, , United Kingdom
Pilgrim Hospital
Boston, , United Kingdom
Royal Bournemouth Hospital
Bournemouth, , United Kingdom
Bradford Royal Infirmary
Bradford, , United Kingdom
Bristol Haematology & Oncology Centre
Bristol, , United Kingdom
Southmead Hospital
Bristol, , United Kingdom
Queen's Hospital
Burton-on-Trent, , United Kingdom
Addenbrooke's Hospital
Cambridge, , United Kingdom
St Helier Hospital
Carshalton, , United Kingdom
Cheltenham General Hospial
Cheltenham, , United Kingdom
Countess of Chester Hospital
Chester, , United Kingdom
Chesterfield Royal Hospital
Chesterfield, , United Kingdom
St Richards Hospital
Chichester, , United Kingdom
University Hospital Coventry
Coventry, , United Kingdom
Royal Derby Hospital
Derby, , United Kingdom
Dewsbury Hospital
Dewsbury, , United Kingdom
Russells Hall Hospital
Dudley, , United Kingdom
Ninewells Hospital
Dundee, , United Kingdom
Hairmyres Hospital
East Kilbride, , United Kingdom
Western General Hospital
Edinburgh, , United Kingdom
Beatson Cancer Centre
Glasgow, , United Kingdom
New Victoria Hospital
Glasgow, , United Kingdom
Gloucestershire Royal Hospital
Gloucester, , United Kingdom
Grantham and District Hospital
Grantham, , United Kingdom
Diana Princess of Wales Hospital
Grimsby, , United Kingdom
Calderdale Royal Hospital
Halifax, , United Kingdom
Harrogate District Hospital
Harrogate, , United Kingdom
Huddersfield Royal Infirmary
Huddersfield, , United Kingdom
Castle Hill Hospital
Hull, , United Kingdom
Raigmore Hospital
Inverness, , United Kingdom
Ipswich Hospital
Ipswich, , United Kingdom
Kidderminster Hospital
Kidderminster, , United Kingdom
University Hospital Crosshouse
Kilmarnock, , United Kingdom
St James's University Hospital
Leeds, , United Kingdom
Leicester Royal Infirmary
Leicester, , United Kingdom
Lincoln County Hospital
Lincoln, , United Kingdom
Royal Liverpool University Hospital
Liverpool, , United Kingdom
University Hospital Aintree
Liverpool, , United Kingdom
Guys and St Thomas's Hospital
London, , United Kingdom
Kings College Hospital
London, , United Kingdom
Royal Marsden Hospital
London, , United Kingdom
St Barts Hospital
London, , United Kingdom
University College London Hospital
London, , United Kingdom
Maidstone Hospital
Maidstone, , United Kingdom
Manchester Royal Infirmary
Manchester, , United Kingdom
The Christie
Manchester, , United Kingdom
Borders General Hospital
Melrose, , United Kingdom
James Cook University Hospital
Middlesbrough, , United Kingdom
Milton Keynes General Hospital
Milton Keynes, , United Kingdom
Freeman Hospital
Newcastle, , United Kingdom
North Tyneside General Hospital
North Shields, , United Kingdom
Norfolk & Norwich University Hospital
Norwich, , United Kingdom
Nottingham City Hospital
Nottingham, , United Kingdom
Royal Oldham Hospital
Oldham, , United Kingdom
Churchill Hospital
Oxford, , United Kingdom
Royal Alexandra Hospital
Paisley, , United Kingdom
Derriford Hospital
Plymouth, , United Kingdom
Pontefract Hospital
Pontefract, , United Kingdom
Whiston Hospital
Prescot, , United Kingdom
Royal Berkshire Hospital
Reading, , United Kingdom
Redditch Hospital
Redditch, , United Kingdom
Tunbridge Wells Hospital
Royal Tunbridge Wells, , United Kingdom
Salford Royal Hospital
Salford, , United Kingdom
Salisbury Hospital
Salisbury, , United Kingdom
Scunthorpe General Hospital
Scunthorpe, , United Kingdom
Royal Hallamshire Hospital
Sheffield, , United Kingdom
Southampton General Hospital
Southampton, , United Kingdom
St Helens Hospital
St Helens, , United Kingdom
Stafford County Hospital
Stafford, , United Kingdom
Stepping Hill Hospital
Stockport, , United Kingdom
Royal Stoke University Hospital
Stoke-on-Trent, , United Kingdom
Sunderland Royal Hospital
Sunderland, , United Kingdom
King's Mill Hospital
Sutton in Ashfield, , United Kingdom
Singleton Hospital
Swansea, , United Kingdom
Musgrove Park Hospital
Taunton, , United Kingdom
St George's Hospital
Tooting, , United Kingdom
Pinderfields General Hospital
Wakefield, , United Kingdom
Royal Hampshire County Hospital
Winchester, , United Kingdom
Wishaw Hospital
Wishaw, , United Kingdom
New Cross Hospital
Wolverhampton, , United Kingdom
Worcestershire Royal Hospital
Worcester, , United Kingdom
Worthing Hospital
Worthing, , United Kingdom
Countries
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Central Contacts
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Facility Contacts
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Jane Tighe
Role: primary
Iain Singer
Role: primary
Paul Micallef-Eynaud
Role: primary
Youssef Sorour
Role: primary
Noel Ryman
Role: primary
Sally Moore
Role: primary
Anand Lokare
Role: primary
Anand Lokare
Role: primary
Mark Cook
Role: primary
Mark Grey
Role: primary
Charlotte Kallmeyer
Role: primary
Rachel Hall
Role: primary
Anshu Garg
Role: primary
James Griffin
Role: primary
Alistair Whiteway
Role: primary
Humayun Ahmad
Role: primary
Charles Crawley
Role: primary
Simon Stern
Role: primary
Michael Shields
Role: primary
Salah Tueger
Role: primary
Rowena Faulkner
Role: primary
Jamie Wilson
Role: primary
Beth Harrison
Role: primary
David Allotey
Role: primary
John Ashcroft
Role: primary
Rupert Hipkins
Role: primary
Duncan Gowans
Role: primary
Iain Singer
Role: primary
Huw Roddie
Role: primary
Grant McQuaker
Role: primary
Ian MacDonald
Role: primary
Michael Shields
Role: primary
Charlotte Kallmeyer
Role: primary
Sanjeev Jalihal
Role: primary
Sylvia Feyler
Role: primary
Tharani Balasubramaniam
Role: primary
Sylvia Feyler
Role: primary
Senthilkumar Durairaj
Role: primary
Peter Forsyth
Role: primary
Debo Ademokun
Role: primary
Saleem Shafik
Role: primary
Paul Micallef-Eynaud
Role: primary
Gordon Cook
Role: primary
Mamta Garg
Role: primary
Charlotte Kallmeyer
Role: primary
Stephen Hawkins
Role: primary
Lynny Young
Role: primary
Majid Kazmi
Role: primary
Majid Kazmi
Role: primary
Kevin Boyd
Role: primary
Jamie Cavenagh
Role: primary
Kwee Yong
Role: primary
Lolita Banerjee
Role: primary
Alberto Rocci
Role: primary
Samar Kulkarni
Role: primary
Jennifer Buxton
Role: primary
Marianna David
Role: primary
Moez Dungarwalla
Role: primary
Graham Jackson
Role: primary
Mari Kilner
Role: primary
Kristian Bowles
Role: primary
Jenny Byrne
Role: primary
Hayley Greenfield
Role: primary
Jam Kothari
Role: primary
Alison Sefcick
Role: primary
Hannah Hunter
Role: primary
John Ashcroft
Role: primary
Toby Nicholson
Role: primary
Henri Grech
Role: primary
Saleem Shafik
Role: primary
Lolita Banerjee
Role: primary
Sonya Ravenscroft
Role: primary
Jonathan Cullis
Role: primary
Sanjeev Jalihal
Role: primary
John Snowden
Role: primary
Matthew Jenner
Role: primary
Toby Nicholson
Role: primary
Kamaraj Karunanithi
Role: primary
Montaser Haj
Role: primary
Kamaraj Karunanithi
Role: primary
Victoria Hervey
Role: primary
Tim Moorby
Role: primary
Hamdi Sati
Role: primary
Simon Bolam
Role: primary
Fenella Willis
Role: primary
John Ashcroft
Role: primary
Noel Ryman
Role: primary
Iain Singer
Role: primary
Supratik Basu
Role: primary
Saleem Shafik
Role: primary
Jamie Wilson
Role: primary
References
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Striha A, Ashcroft AJ, Hockaday A, Cairns DA, Boardman K, Jacques G, Williams C, Snowden JA, Garg M, Cavenagh J, Yong K, Drayson MT, Owen R, Cook M, Cook G. The role of ixazomib as an augmented conditioning therapy in salvage autologous stem cell transplant (ASCT) and as a post-ASCT consolidation and maintenance strategy in patients with relapsed multiple myeloma (ACCoRd [UK-MRA Myeloma XII] trial): study protocol for a Phase III randomised controlled trial. Trials. 2018 Mar 7;19(1):169. doi: 10.1186/s13063-018-2524-8.
Related Links
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Myeloma XII protocol paper
Other Identifiers
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2016-000905-35
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
HM16/047
Identifier Type: -
Identifier Source: org_study_id
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