The Role of Ixazomib in Autologous Stem Cell Transplant in Relapsed Myeloma - Myeloma XII (ACCoRd)
ConditionMultiple Myeloma
Trial statusRecruiting
Trial phasePhase 3
Trial typeInterventional
Biological sexAll
Age18+
SponsorUniversity of Leeds
About this trial
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
This trial does not accept healthy volunteersQualifiers
Diagnosed with relapsed MM (with measurable disease, according to IMWG criteria (Appendix 2)) previously treated with ASCT).
First Progressive Disease (PD) at least 12 months following first ASCT, requiring therapy.
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 (Appendix 3).
Aged at least 18 years.
Disqualifiers
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.
≥Grade 2 peripheral neuropathy within 14 days before registration.
Known HIV seropositivity.
Known resistance, intolerance or sensitivity to any component of the planned therapies.
Trial design
Design model
Parallel
Treatments tested in this trial
Ixazomib, thalidomide, & dexamethasone (ITD) re-induction
Drug4 - 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)
DrugMelphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0.
Augmented autologous stem cell transplant (ASCT-aug)
DrugMelphalan 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
DrugParticipants 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.
Treatment groups
406 Participants
are divided into 2 treatment groupsGroup A: Conventional Autologous Stem Cell Transplant (ASCT)Active comparator 3 interventions
Group B: Augmented Autologous Stem Cell Transplant (ASCT)Experimental treatment 3 interventions
Trial outcomes
Primary outcomes
1
Overall response rate
Overall response rate following ASCT will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma. This endpoint will be defined as a binary dichotomization of response (≥VGPR vs \<VGPR) at an assessment 100 days after the date of stem cell transplant.
Time frame
100 days post-ASCT2
Progression-free survival
The influence of a consolidation and maintenance strategy on the Durability of Response (DuR: PFS)
Time frame
From date of registration to date of disease progression, up to 120 months.Secondary outcomes
1
Overall survival
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.
Time frame
From date of R2 to date of death, up to 120 months2
Time to disease progression
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.
Time frame
From date of registration until date of disease progression, up to 120 months3
Overall response rate to ITD re-induction
Overall response rate following re-induction will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma.
Time frame
At the end of re-induction - after 4-6 re-induction cycles (each cycle is 28 days)4
Upgrade in response after two cycles of ITD consolidation
Upgrade in response after 2 cycles of ITD consolidation - response rate following ITD consolidation will be determined according to the IMWG Uniform Response Criteria for Multiple Myeloma. This endpoint will be defined as a binary dichotomization of response (≥VGPR vs \<VGPR).
Time frame
After 2 cycles of ITD consolidation (each cycle is 28 days)Other outcomes
1
Cytogenetics_composite measure
Cytogenetic subgroups will be analysed to explore a number of specific hypotheses, including the effect on PFS, OS, TTP and response (≥VGPR vs. \<VGPR). Some examples of what will be studied include chromosome 14 translocations and abnormalities of chromosome 1p, 1q, 13q and 17p. In addition, other regions considered to be of interest will be analysed according to the statistical analysis plan. Other subgroup and exploratory analyses may also be carried out and will be described in the statistical analysis plan or separate analyses plans related to translational work.
Time frame
Through study completion, up to 120 monthsSponsors and contacts
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Source ClinicalTrials.gov