Condition category
Cancer
Date applied
28/11/2016
Date assigned
15/12/2016
Last edited
09/03/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Scientific

Primary contact

Dr Gwen Jacques

ORCID ID

Contact details

University of Leeds
Leeds
LS2 9JT
United Kingdom
+44 (0)113 343 1159
ctru-myelomaxii@leeds.ac.uk

Additional identifiers

EudraCT number

2016-000905-35

ClinicalTrials.gov number

Protocol/serial number

32907

Study information

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

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

North West - Greater Manchester South Research Ethics Committee, 11/10/2016, ref: 16/NW/0517

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

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

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

Phase

Phase III

Drug names

Ixazomib, thalidomide, dexamethasone, melphalan

Primary 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 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 trial start date

01/01/2016

Overall trial end date

31/01/2026

Reason abandoned

Eligibility

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 type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 406; UK Sample Size: 406

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

01/01/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

St James’s University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Arrowe Park Hospital
Arrowe Park Road Upton Birkenhead
Wirral
CH49 5PE
United Kingdom

Trial participating centre

Barnsley Hospital
Gawber Road
Barnsley
S75 2EP
United Kingdom

Trial participating centre

Basingstoke and North Hampshire Hospital
Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Trial participating centre

Beatson West of Scotland Cancer Centre
Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Belfast City Hospital
Lisburn Road
Belfast
BT9 7AB
United Kingdom

Trial participating centre

Birmingham Heartlands Hospital
Bordesley Green E
Birmingham
B9 5SS
United Kingdom

Trial participating centre

Blackpool Victoria Hospital
Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom

Trial participating centre

Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Trial participating centre

Bristol Haematology and Oncology Centre
Horfield Road
Bristol
BS2 8ED
United Kingdom

Trial participating centre

Calderdale Royal Hospital
Salterhebble
Halifax
HX3 0PW
United Kingdom

Trial participating centre

Chesterfield Royal Infirmary
Chesterfield Road Calow
Chesterfield
S44 5BL
United Kingdom

Trial participating centre

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

Trial participating centre

Darent Valley Hospital
Darenth Wood Road
Dartford
DA2 8DA
United Kingdom

Trial participating centre

Derriford Hospital
Derriford Road
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

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

Trial participating centre

Good Hope Hospital
Rectory Road
Sutton Coldfield
B75 7RR
United Kingdom

Trial participating centre

Grantham and District Hospital
101 Manthorpe Road
Grantham
NG31 8DG
United Kingdom

Trial participating centre

Huddersfield Royal Infirmary
Acre Street Lindley
Huddersfield
HD3 3EA
United Kingdom

Trial participating centre

Ipswich Hospital
Heath Road
Ipswich
IP4 5PD
United Kingdom

Trial participating centre

James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
United Kingdom

Trial participating centre

John Radcliffe Hospital
Headley Way
Oxford
OX3 9DU
United Kingdom

Trial participating centre

King’s Mill Hospital
Mansfield Road
Sutton-in-Ashfield
NG17 4JL
United Kingdom

Trial participating centre

Leicester Royal Infirmary
Infirmary Square
Leicester
LE1 5WW
United Kingdom

Trial participating centre

Lincoln County Hospital
Greetwell Road
Lincoln
LN2 5QY
United Kingdom

Trial participating centre

Maidstone Hospital
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Trial participating centre

Milton Keynes General Hospital
Standing Way Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

Trial participating centre

Monklands Hospital
Monkscourt Avenue
Airdrie
ML6 0JS
United Kingdom

Trial participating centre

Ninewells Hospital
NHS Tayside
Dundee
DD1 9SY
United Kingdom

Trial participating centre

Norfolk & Norwich University Hospital
Colney Lane
Norwich
NR4 7UY
United Kingdom

Trial participating centre

North Tyneside General Hospital
Rake Lane
North Shields
NE29 8NH
United Kingdom

Trial participating centre

Nottingham City Hospital
Hucknall Road
Nottingham
NG5 1PB
United Kingdom

Trial participating centre

Pilgrim Hospital
Sibsey Road
Boston
PE21 9QS
United Kingdom

Trial participating centre

Pinderfields General Hospital
Aberford Road
Wakefield
WF1 4DG
United Kingdom

Trial participating centre

Queen Elizabeth Hospital Birmingham
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Trial participating centre

Queen’s Hospital
Belvedere Road
Burton-on-Trent
DE13 0RB
United Kingdom

Trial participating centre

Royal Alexandra Hospital
Corsebar Road
Paisley
PA2 9PN
United Kingdom

Trial participating centre

Royal Derby Hospital
Uttoxeter Road
Derby
DE22 3NE
United Kingdom

Trial participating centre

Royal Hallamshire Hospital
Glossop Road
Sheffield
S10 2JF
United Kingdom

Trial participating centre

Royal Hampshire County Hospital
Romsey Road
Winchester
SO22 5DG
United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

Royal Marsden Hospital
Fulham Road Chelsea
London
SW3 6JJ
United Kingdom

Trial participating centre

Royal Stoke University Hospital
Newcastle Road
Stoke-on-Trent
ST4 6QG
United Kingdom

Trial participating centre

Royal United Hospital
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Russells Hall Hospital
Pensnett Road
Dudley
DY1 2HQ
United Kingdom

Trial participating centre

Salisbury District Hospital
Odstock Road
Salisbury
SP2 8BJ
United Kingdom

Trial participating centre

Stepping Hill Hospital
Poplar Grove Hazel Grove
Stockport
SK2 7JE
United Kingdom

Trial participating centre

St Bartholomew’s Hospital
W Smithfield
London
EC1A 7BE
United Kingdom

Trial participating centre

St George’s Hospital
Blackshaw Road Tooting
London
SW17 0QT
United Kingdom

Trial participating centre

St Helens Hospital
Marshalls Cross Road
St. Helens
WA9 3D
United Kingdom

Trial participating centre

St Helier Hospital
Wrythe Lane Sutton
Carshalton
SM5 1AA
United Kingdom

Trial participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Sunderland Royal Hospital
Kayll Road
Sunderland
SR4 7TP
United Kingdom

Trial participating centre

The Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

The Christie
550 Wilmslow Road
Manchester
M20 4BX
United Kingdom

Trial participating centre

Torbay Hospital
Newton Road
Torquay
TQ2 7AA
United Kingdom

Trial participating centre

Tunbridge Wells Hospital
Tonbridge Road
Tunbridge Wells
TN2 4QJ
United Kingdom

Trial participating centre

University College London Hospital
235 Euston Road
London
NW1 2BU
United Kingdom

Trial participating centre

University Hospital Aintree
Longmoor Lane
Liverpool
L9 7AL
United Kingdom

Trial participating centre

University Hospital Ayr
Dalmellington Road
Ayr
KA6 6DX
United Kingdom

Trial participating centre

University Hospital Crosshouse
Kilmarnock Road Crosshouse
Kilmarnock
KA2 0BE
United Kingdom

Trial participating centre

Worcestershire Royal Hospital
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom

Sponsor information

Organisation

University of Leeds

Sponsor details

-
Leeds
LS2 9JT
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Charity

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Funder name

Takeda Development Center Americas, Inc.

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

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.

Intention to publish date

31/01/2027

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

2018 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/29514706

Publication citations

Additional files

Editorial Notes

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.