Myeloma XII (ACCoRd trial)

ISRCTN	ISRCTN10038996
DOI	https://doi.org/10.1186/ISRCTN10038996
EudraCT/CTIS number	2016-000905-35
Secondary identifying numbers	32907

Submission date: 28/11/2016
Registration date: 15/12/2016
Last edited: 10/09/2024

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

http://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-ixazomib-for-people-with-myeloma-that-has-come-back-myeloma-xii-accord

Contact information

Dr Gwen Jacques
Scientific

University of Leeds
Leeds
LS2 9JT
United Kingdom

Phone	+44 (0)113 343 1159
Email	ctru-myelomaxii@leeds.ac.uk

Study information

Study design	Randomised; Interventional; Design type: Treatment, Drug
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	Myeloma XII (ACCoRd): A phase III study to determine 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
Study acronym	ACCoRd
Study hypothesis	This trial aims to determine and compare: 1. The depth of response between standard melphalan conditioning and augmented (adding ixazomib) melphalan conditioning at second ASCT 2. The impact of adding consolidation and maintenance treatment versus no further treatment, on progression free survival
Ethics approval(s)	North West - Greater Manchester South Research Ethics Committee, 11/10/2016, ref: 16/NW/0517
Condition	Multiple myeloma
Intervention	Participants are randomised in a 1:1 ratio to receive 2 cycles ITD. ITD re-induction therapy All participants will be registered at trial entry and will receive re-induction therapy with 4-6 cycles of ixazomib, thalidomide, and dexamethasone (ITD), as per the dosing regimen below: Cycles 1-6 of ITD re-induction (28-day cycles) Ixazomib: 4mg/day on days 1, 8, 15, taken orally Thalidomide: 100mg/day on days 1-28, taken orally Dexamethasone: 40mg/day on days 1, 8, 15, 22, taken orally Response assessment after ITD re-induction to determine eligibility for Randomisation 1, according to International Myeloma Working Group criteria. Randomisation 1 Eligible participants who reach at least stable disease after ITD re-induction will be randomised on a 1:1 basis to receive either (a) conventional autologous stem cell transplant (ASCT-con) using melphalan, or (b) augmented autologous stem cell transplant (ASCT-aug) using melphalan with ixazomib. Dosing regimens below: ASCT-con: Melphalan 200mg/m2/day on D-1, intravenously ASCT on D0 ASCT-aug: Ixazomib 4mg/day on D-4 and D-1, taken orally Melphalan 100mg/m2/day on D-3 and D-2, intravenously ASCT on D0 Response assessment 100 days after ASCT-con or ASCT-aug to determine eligibility for Randomisation 2, according to International Myeloma Working Group criteria. Randomisation 2 (R2) Eligible participants who reach at least minimum response 100 days after ASCT-con or ASCT-aug will be randomised on a 1:1 basis to receive either (a) ITD consolidation and ixazomib maintenance, or (b) no further therapy. If participants are randomised to receive further therapy, the dosing regimens are below: 2 cycles of ITD consolidation (28-day cycles): Ixazomib: 4mg/day on days 1, 8, 15, taken orally Thalidomide: 100mg/day on days 1-28, taken orally Dexamethasone: 40mg/day on days 1, 8, 15, 22, taken orally Ixazomib maintenance, taken until disease progression (28-day cycles): Ixazomib: 4mg/day on days 1, 8, 15, taken orally For participants randomised to further therapy at R2, follow-up will be done at the end of consolidation and subsequently at 3-monthly intervals (starting from 3 months post-R2). For participants randomised to no further therapy at R2, follow-up will be done at 8 weeks post-R2 and subsequently 3-monthly visits (starting from 3 months post R2) thereafter until disease progression. Following disease progression, follow-up will be done annually post-progression until death.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase III
Drug / device / biological / vaccine name(s)	Ixazomib, thalidomide, dexamethasone, melphalan
Primary outcome measure	All outcome measures are measured at baseline, the end of each re-induction cycle, the end of re-induction, 100 days post-ASCT, the end of consolidation, 8 weeks post-randomisation 2, 3 monthly post randomisation-2 until disease progression and at the time of disease progression: 1. Overall response rate following ASCT, defined as the impact on Depth of Response (DoR: <VGPR vs. ≥VGPR) when salvage ASCT conditioning is augmented by the addition of a proteasome inhibitor, will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma 2. Progression-free survival, is defined as the time from randomisation to the consolidation part of the trial to first documented evidence of disease progression or death from any cause. Participants who do not progress will be censored at the last date they were known to be alive and progression free
Secondary outcome measures	All outcome measures are measured at baseline, the end of each re-induction cycle, the end of re-induction, 100 days post-ASCT, the end of consolidation, 8 weeks post-randomisation 2, 3 monthly post randomisation-2 until disease progression and at the time of disease progression: 1. Overall survival is defined as the time from randomisation to the consolidation/ maintenance part of the trial post-ASCT to death from any cause or last follow-up 2. Time to disease progression is defined as time from randomisation to the consolidation/ maintenance part of the trial post-ASCT to first documented evidence of disease progression. Participants who die without disease progression will be censored in the analysis. 3. Overall response rate following re-induction will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma 4. Progression-free survival 2 is defined as the time from second randomisation to the consolidation/maintenance part of the trial post-ASCT to second documented disease progression (or the start of next line anti-myeloma treatment), or death from any cause, whichever occurs first. Participants alive and for whom a second progression after second randomisation has not been observed will be censored at the last day they were known to be alive and second progression-free. 5. Time to next line treatment is defined as the time from the date of randomisation to the date of commencement of next line treatment. Participants who do not receive next line treatment will be censored at the date of the last assessment or follow-up visit where they are known to have received no new therapy. 6. Duration of response to protocol treatment is defined from the time of achieving at least a partial response to the date of first documented evidence of disease progression. Participants who die prior to documentation of disease progression will be censored at the date of death. Participants dying from causes not primarily due to progression will also be censored at the date of death. Participants not reaching disease progression at the time of analysis will be censored at the last date known to be progression-free. 7. Engraftment kinetics will be summarised based on summaries of stem cell remobilisation protocol and success of remobilisation and stem cell harvest after the completion of ASCT for all participants 8. Rate of Minimal Residual Disease negativity is defined as the proportion of participants with minimal residual disease (MRD) as assessed by flow cytometry will be assessed at various points in trial protocol treatment 9. Toxicity and safety will be reported based on adverse events, as graded by CTCAE V4.03 and determined by routine clinical assessments at each centre 10. Quality of Life (QoL) i.e. EORTC QLQ-C30, EORTC QLQ-MY20, and the EQ-5D will be used to measure participant-assessed QoL at registration, post re-induction, 100 days post-ASCT and annually post second randomisation until 24 months post second randomisation, or until disease progression whichever is earlier
Overall study start date	01/01/2016
Overall study end date	30/04/2027

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 406; UK Sample Size: 406
Participant inclusion criteria	1. Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria) previously treated with ASCT 2. First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 4. Aged at least 18 years 5. Participants must have the following blood results within 14 days before registration: a. Absolute neutrophil count (ANC) ≥1x109/L b.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 Cockcroft-Gault equation or other locally approved formula) 7. Adequate hepatobiliary function within 14 days before registration: a. Total bilirubin <2 x upper limit of normal (ULN) b. 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: 10.1. Are not of childbearing potential (Appendix 8), OR 10.2. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent form until 90 days after the last dose of study drug, OR 10.3. 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: a. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR b. 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
Participant exclusion criteria	1. Received prior second line therapy for their relapsed disease other than local radiotherapy, therapeutic plasma exchange, or dexamethasone (up to a maximum of 200mg is allowed but not within 30 days prior to registration). Radiotherapy sufficient to alleviate or control pain of local invasion is permitted, but must not be within 14 days before registration. Patients who have received hemi-body radiation or similar since relapse will not be eligible 2. ≥Grade 2 peripheral neuropathy within 14 days before registration 3. Known HIV or Hepatitis B/C 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. less than or equal to Grade 1 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
Recruitment start date	20/03/2017
Recruitment end date	31/05/2022

Locations

Countries of recruitment

England
Northern Ireland
Scotland
United Kingdom

Study participating centres

St James’s University Hospital

Beckett Street
Leeds
LS9 7TF
United Kingdom

Addenbrookes Hospital

Hills Road
Cambridge
CB2 0QQ
United Kingdom

Arrowe Park Hospital

Arrowe Park Road
Upton
Birkenhead
Wirral
CH49 5PE
United Kingdom

Barnsley Hospital

Gawber Road
Barnsley
S75 2EP
United Kingdom

Basingstoke and North Hampshire Hospital

Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Beatson West of Scotland Cancer Centre

Great Western Road
Glasgow
G12 0YN
United Kingdom

Belfast City Hospital

Lisburn Road
Belfast
BT9 7AB
United Kingdom

Birmingham Heartlands Hospital

Bordesley Green E
Birmingham
B9 5SS
United Kingdom

Blackpool Victoria Hospital

Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Bradford Royal Infirmary

Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Bristol Haematology and Oncology Centre

Horfield Road
Bristol
BS2 8ED
United Kingdom

Calderdale Royal Hospital

Salterhebble
Halifax
HX3 0PW
United Kingdom

Chesterfield Royal Infirmary

Chesterfield Road
Calow
Chesterfield
S44 5BL
United Kingdom

Countess of Chester

The Countess Of Chester Health Park
Liverpool Road
Chester
CH2 1UL
United Kingdom

Darent Valley Hospital

Darenth Wood Road
Dartford
DA2 8DA
United Kingdom

Derriford Hospital

Derriford Road
Plymouth
PL6 8DH
United Kingdom

Freeman Hospital

Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Good Hope Hospital

Rectory Road
Sutton Coldfield
B75 7RR
United Kingdom

Grantham and District Hospital

101 Manthorpe Road
Grantham
NG31 8DG
United Kingdom

Huddersfield Royal Infirmary

Acre Street
Lindley
Huddersfield
HD3 3EA
United Kingdom

Ipswich Hospital

Heath Road
Ipswich
IP4 5PD
United Kingdom

James Cook University Hospital

Marton Road
Middlesbrough
TS4 3BW
United Kingdom

John Radcliffe Hospital

Headley Way
Oxford
OX3 9DU
United Kingdom

King’s Mill Hospital

Mansfield Road
Sutton-in-Ashfield
NG17 4JL
United Kingdom

Leicester Royal Infirmary

Infirmary Square
Leicester
LE1 5WW
United Kingdom

Lincoln County Hospital

Greetwell Road
Lincoln
LN2 5QY
United Kingdom

Maidstone Hospital

Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Milton Keynes General Hospital

Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

Monklands Hospital

Monkscourt Avenue
Airdrie
ML6 0JS
United Kingdom

Ninewells Hospital

NHS Tayside
Dundee
DD1 9SY
United Kingdom

Norfolk & Norwich University Hospital

Colney Lane
Norwich
NR4 7UY
United Kingdom

North Tyneside General Hospital

Rake Lane
North Shields
NE29 8NH
United Kingdom

Nottingham City Hospital

Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Pilgrim Hospital

Sibsey Road
Boston
PE21 9QS
United Kingdom

Pinderfields General Hospital

Aberford Road
Wakefield
WF1 4DG
United Kingdom

Queen Elizabeth Hospital Birmingham

Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Queen’s Hospital

Belvedere Road
Burton-on-Trent
DE13 0RB
United Kingdom

Royal Alexandra Hospital

Corsebar Road
Paisley
PA2 9PN
United Kingdom

Royal Derby Hospital

Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Royal Hallamshire Hospital

Glossop Road
Sheffield
S10 2JF
United Kingdom

Royal Hampshire County Hospital

Romsey Road
Winchester
SO22 5DG
United Kingdom

Royal Liverpool University Hospital

Prescot Street
Liverpool
L7 8XP
United Kingdom

Royal Marsden Hospital

Fulham Road
Chelsea
London
SW3 6JJ
United Kingdom

Royal Stoke University Hospital

Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Royal United Hospital

Combe Park
Bath
BA1 3NG
United Kingdom

Russells Hall Hospital

Pensnett Road
Dudley
DY1 2HQ
United Kingdom

Salisbury District Hospital

Odstock Road
Salisbury
SP2 8BJ
United Kingdom

Stepping Hill Hospital

Poplar Grove
Hazel Grove
Stockport
SK2 7JE
United Kingdom

St Bartholomew’s Hospital

W Smithfield
London
EC1A 7BE
United Kingdom

St George’s Hospital

Blackshaw Road
Tooting
London
SW17 0QT
United Kingdom

St Helens Hospital

Marshalls Cross Road
St. Helens
WA9 3D
United Kingdom

St Helier Hospital

Wrythe Lane
Sutton
Carshalton
SM5 1AA
United Kingdom

Southampton General Hospital

Tremona Road
Southampton
SO16 6YD
United Kingdom

Sunderland Royal Hospital

Kayll Road
Sunderland
SR4 7TP
United Kingdom

The Beatson West of Scotland Cancer Centre

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

The Christie

550 Wilmslow Road
Manchester
M20 4BX
United Kingdom

Torbay Hospital

Newton Road
Torquay
TQ2 7AA
United Kingdom

Tunbridge Wells Hospital

Tonbridge Road
Tunbridge Wells
TN2 4QJ
United Kingdom

University College London Hospital

235 Euston Road
London
NW1 2BU
United Kingdom

University Hospital Aintree

Longmoor Lane
Liverpool
L9 7AL
United Kingdom

University Hospital Ayr

Dalmellington Road
Ayr
KA6 6DX
United Kingdom

University Hospital Crosshouse

Kilmarnock Road
Crosshouse
Kilmarnock
KA2 0BE
United Kingdom

Worcestershire Royal Hospital

Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Sponsor information

University of Leeds
University/education

-
Leeds
LS2 9JT
England
United Kingdom

"ROR"	https://ror.org/024mrxd33

Funders

Funder type

Charity

Cancer Research UK
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Takeda Development Center Americas, Inc.

No information available

Results and Publications

Intention to publish date	30/04/2028
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal, 12 months after the trial ends.
IPD sharing plan	The current data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	07/03/2018		Yes	No
HRA research summary			26/07/2023	No	No
Results article		06/09/2024	10/09/2024	Yes	No

Editorial Notes

10/09/2024: Publication reference added.
23/11/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/01/2022 to 31/05/2022.
2. The overall end date was changed from 31/01/2026 to 30/04/2027.
3. The intention to publish date was changed from 31/01/2027 to 30/04/2028.
20/09/2021: Internal review.
28/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissu" to "Multiple myeloma" following a request from the NIHR.
09/03/2018: Publication reference added.
25/05/2017: Cancer Help UK lay summary link added to plain English summary field.
23/03/2017: The recruitment start date has been updated from 15/02/2017 to 20/03/2017.
23/01/2017: The recruitment start date has been updated from 01/01/2017 to 15/02/2017.