A Phase 3 interventional study of Ixazomib, thalidomide, & dexamethasone (ITD) re-induction and Conventional autologous stem cell transplant (ASCT-con) in Multiple Myeloma, sponsored by University of Leeds. Recruiting at 91 sites in United Kingdom. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-06-19.
Sponsored by University of Leeds · Phase 3, Interventional, and Treatment
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:
Secondary objectives
The secondary objectives of this study are to determine:
Participant population (refer to protocol section 9 for a full list of eligibility criteria).
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).
3,632 studies on the registry are indexed under Multiple Myeloma; 745 are open to participants now.
This study's planned enrollment of 406 is above the median of 41 across 2,907 interventional studies indexed under Multiple Myeloma.
Browse Multiple Myeloma studies →University of Leeds is the lead sponsor of 200 studies on the registry; 25 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Participants must have the following blood results within 14 days before registration:
Platelet transfusions are not allowed within 3 days before registration in order to meet these values.
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)
Adequate hepatobiliary function within 14 days before registration:
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.
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.
Female participants who:
Male participants, even if surgically sterilised (i.e. status post-vasectomy), must agree to one of the following:
Exclusion Criteria:
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0
Drug: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction · Drug: Conventional autologous stem cell transplant (ASCT-con) · Drug: ITD consolidation and ixazomib maintenance vs. No further therapy
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.
Drug: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction · Drug: Augmented autologous stem cell transplant (ASCT-aug) · Drug: ITD consolidation and ixazomib maintenance vs. No further therapy
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
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0.
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.
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.
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-ASCT
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.
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 months
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 months
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)
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)
Progression-free survival 2 (PFS2)
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.
Time frame: Date of R2 to date of second disease progression, up to 120 months
Time to next treatment
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.
Time frame: Date of registration to start date of new therapy, up to 120 months
Duration of response
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.
Time frame: Date of achieving at least partial response to date of disease progression, up to 120 months
Proportion of patients Minimal Residual Disease negative
Proportion of patients Minimal Residual Disease negative is defined as the proportion of participants with minimal residual disease (MRD) negative as assessed by flow cytometry will be assessed at various points in trial protocol treatment.
Time frame: 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
Continuous Minimal Residual Disease (MRD)
Continuous Minimal Residual Disease (MRD) measurements as assessed by flow cytometry will be assessed at various points in trial protocol treatment.
Time frame: 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
Engraftment kinetics_test
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.
Time frame: Stem cell harvest; 100 days post-ASCT
Incidence of treatment-emergent adverse events (Toxicity and safety)
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.
Time frame: 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
EORTC QLQ-C30_questionnaire
The EORTC QLQ-C30 questionnaire will be used to measure participant-assessed quality of life 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.
Time frame: 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
EORTC QLQ-MY20_questionnaire
The EORTC QLQ-MY20 questionnaire will be used to measure participant-assessed quality of life 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.
Time frame: 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
EQ-5D_questionnaire
The EQ-5D questionnaire will be used to measure participant-assessed quality of life 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.
Time frame: 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
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 months
Plan to share: Undecided
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