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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 406
- 试验地点
- 91
- 主要终点
- Overall response rate
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Participants must have the following blood results within 14 days before registration:
- •Absolute neutrophil count (ANC) ≥1x109/L
- •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.
- •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:
- •Total bilirubin <2 x upper limit of normal (ULN)
- •ALT <2 x ULN
- •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:
- •Are not of childbearing potential (Appendix 8), OR
- •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
- •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:
- •Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, OR
- •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.
- •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.
- •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.
- •Able to provide written informed consent.
排除标准
- •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.
- •Any medical or psychiatric condition which, in the opinion of the investigator, contraindicates the participant's participation in this study.
- •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).
- •Pregnant, lactating or breast feeding female participants.
- •Failure to have fully recovered (i.e.Grade 1 or less toxicity) from the reversible effects of prior chemotherapy.
- •Major surgery within 14 days before registration.
- •Central nervous system involvement with myeloma.
- •Ongoing or active infection requiring systemic antibiotic therapy or other serious infection within 14 days before registration.
- •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.
- •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.
- •Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib, including difficulty swallowing.
- •Patients that have previously been treated with ixazomib or participated in a study with ixazomib whether treated with ixazomib or not.
- •Participant has current or prior hepatitis B or C infection.
研究组 & 干预措施
Augmented Autologous Stem Cell Transplant (ASCT)
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.
干预措施: Augmented autologous stem cell transplant (ASCT-aug) (Drug)
Conventional Autologous Stem Cell Transplant (ASCT)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0
干预措施: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction (Drug)
Conventional Autologous Stem Cell Transplant (ASCT)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0
干预措施: Conventional autologous stem cell transplant (ASCT-con) (Drug)
Conventional Autologous Stem Cell Transplant (ASCT)
Melphalan 200mg/m2 IV infusion on Day -1, followed by ASCT on Day 0
干预措施: ITD consolidation and ixazomib maintenance vs. No further therapy (Drug)
Augmented Autologous Stem Cell Transplant (ASCT)
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.
干预措施: Ixazomib, thalidomide, & dexamethasone (ITD) re-induction (Drug)
Augmented Autologous Stem Cell Transplant (ASCT)
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.
干预措施: ITD consolidation and ixazomib maintenance vs. No further therapy (Drug)
结局指标
主要结局
Overall response rate
时间窗: 100 days post-ASCT
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.
Progression-free survival
时间窗: From date of registration to date of disease progression, up to 120 months.
The influence of a consolidation and maintenance strategy on the Durability of Response (DuR: PFS)
次要结局
- Overall survival(From date of R2 to date of death, up to 120 months)
- Time to disease progression(From date of registration until date of disease progression, up to 120 months)
- Overall response rate to ITD re-induction(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(After 2 cycles of ITD consolidation (each cycle is 28 days))
- Progression-free survival 2 (PFS2)(Date of R2 to date of second disease progression, up to 120 months)
- Time to next treatment(Date of registration to start date of new therapy, up to 120 months)
- Duration of response(Date of achieving at least partial response to date of disease progression, up to 120 months)
- Proportion of patients Minimal Residual Disease negative(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)(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(Stem cell harvest; 100 days post-ASCT)
- Incidence of treatment-emergent adverse events (Toxicity and safety)(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(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(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(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)