Clinical trial NCT03562169: The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)
Official title: 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 type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Lead sponsor: University of Leeds
Sponsor class: OTHER
Collaborators: name: Cancer Research UK
name: Takeda
First posted: 2018-06-19
Enrollment: 406
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study design: Randomised, controlled, multi-centre, open-label, phase III trial (with a single intervention registration phase).

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).


Eligibility criteria: Inclusion Criteria:

1. Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) 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 (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:

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 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.

Primary outcomes:
measure: Overall response rate
timeFrame: 100 days post-ASCT
measure: Progression-free survival
timeFrame: From date of registration to date of disease progression, up to 120 months.
Secondary outcomes:
measure: Overall survival
timeFrame: From date of R2 to date of death, up to 120 months
measure: Time to disease progression
timeFrame: From date of registration until date of disease progression, up to 120 months
measure: Overall response rate to ITD re-induction
timeFrame: At the end of re-induction - after 4-6 re-induction cycles (each cycle is 28 days)
measure: Upgrade in response after two cycles of ITD consolidation
timeFrame: After 2 cycles of ITD consolidation (each cycle is 28 days)
measure: Progression-free survival 2 (PFS2)
timeFrame: Date of R2 to date of second disease progression, up to 120 months
measure: Time to next treatment
timeFrame: Date of registration to start date of new therapy, up to 120 months
measure: Duration of response
timeFrame: Date of achieving at least partial response to date of disease progression, up to 120 months
measure: Proportion of patients Minimal Residual Disease negative
timeFrame: Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; After 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-randomisation 2; 12 months post-randomisation 2
measure: Continuous Minimal Residual Disease (MRD)
timeFrame: Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; After 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-randomisation 2; 12 months post-randomisation 2
measure: Engraftment kinetics_test
timeFrame: Stem cell harvest; 100 days post-ASCT
measure: Incidence of treatment-emergent adverse events (Toxicity and safety)
timeFrame: Baseline; End of each re-induction cycle (each cycle is 28 days); 100 days post-ASCT; End of 2 cycles of consolidation (each cycle is 28 days); 8 weeks post-R2; 3 monthly post-R2 until disease progression; Disease progression, up to 120 months
measure: EORTC QLQ-C30_questionnaire
timeFrame: Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2
measure: EORTC QLQ-MY20_questionnaire
timeFrame: Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2
measure: EQ-5D_questionnaire
timeFrame: Baseline; End of re-induction (after 4-6 cycles of re-induction, each cycle is 28 days); 100 days post-ASCT; 12 months post-R2; 24 months post-R2
Other outcomes:
measure: Cytogenetics_composite measure
timeFrame: Through study completion, up to 120 months
Locations:
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Airdrie
country: United Kingdom
facility: Monklands Hospital
city: Ayr
country: United Kingdom
facility: University Hospital Ayr
city: Barnsley
country: United Kingdom
facility: Barnsley Hospital
city: Basingstoke
country: United Kingdom
facility: Basingstoke & North Hampshire Hospital
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Birmingham
country: United Kingdom
facility: Good Hope Hospital
city: Birmingham
country: United Kingdom
facility: Heartlands Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
city: Boston
country: United Kingdom
facility: Pilgrim Hospital
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology Centre
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Burton Upon Trent
country: United Kingdom
facility: Queen's Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Carshalton
country: United Kingdom
facility: St Helier Hospital
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospial
city: Chesterfield
country: United Kingdom
facility: Chesterfield Royal Hospital
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
city: Chichester
country: United Kingdom
facility: St Richards Hospital
city: Coventry
country: United Kingdom
facility: University Hospital Coventry
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Dewsbury
country: United Kingdom
facility: Dewsbury Hospital
city: Dudley
country: United Kingdom
facility: Russells Hall Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: East Kilbride
country: United Kingdom
facility: Hairmyres Hospital
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson Cancer Centre
city: Glasgow
country: United Kingdom
facility: New Victoria Hospital
city: Gloucester
country: United Kingdom
facility: Gloucestershire Royal Hospital
city: Grantham
country: United Kingdom
facility: Grantham and District Hospital
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales Hospital
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
city: Harrogate
country: United Kingdom
facility: Harrogate District Hospital
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Kidderminster
country: United Kingdom
facility: Kidderminster Hospital
city: Kilmarnock
country: United Kingdom
facility: University Hospital Crosshouse
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: Liverpool
country: United Kingdom
facility: University Hospital Aintree
city: London
country: United Kingdom
facility: Guys and St Thomas's Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: London
country: United Kingdom
facility: St Barts Hospital
city: London
country: United Kingdom
facility: University College London Hospital
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Manchester
country: United Kingdom
facility: The Christie
city: Melrose
country: United Kingdom
facility: Borders General Hospital
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes General Hospital
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: North Shields
country: United Kingdom
facility: North Tyneside General Hospital
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oldham
country: United Kingdom
facility: Royal Oldham Hospital
city: Oxford
country: United Kingdom
facility: Churchill Hospital
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Pontefract
country: United Kingdom
facility: Pontefract Hospital
city: Prescot
country: United Kingdom
facility: Whiston Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Redditch
country: United Kingdom
facility: Redditch Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Salisbury
country: United Kingdom
facility: Salisbury Hospital
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: St Helens
country: United Kingdom
facility: St Helens Hospital
city: Stafford
country: United Kingdom
facility: Stafford County Hospital
city: Stockport
country: United Kingdom
facility: Stepping Hill Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
city: Sutton In Ashfield
country: United Kingdom
facility: King's Mill Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
city: Tooting
country: United Kingdom
facility: St George's Hospital
city: Tunbridge Wells
country: United Kingdom
facility: Tunbridge Wells Hospital
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
city: Wishaw
country: United Kingdom
facility: Wishaw Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
city: Worcester
country: United Kingdom
facility: Worcestershire Royal Hospital
city: Worthing
country: United Kingdom
facility: Worthing Hospital
Study officials:
affiliation: Univeristy of Leeds, CTRU
name: Head of Trial Management
role: STUDY_DIRECTOR
References:
citation: 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.