A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of Oral Ixazomib Citrate (MLN9708) Maintenance Therapy in Patients With Multiple Myeloma Following Autologous Stem Cell Transplant
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 656
- 试验地点
- 227
- 主要终点
- Progression Free Survival (PFS)
研究概览
简要总结
The purpose of this study is to determine the effect of ixazomib citrate maintenance therapy on progression-free survival (PFS), compared to placebo, in participants with newly diagnosed multiple myeloma (NDMM) who have had a response (complete response [CR], very good partial response [VGPR], or partial response [PR]) to induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT).
详细描述
The investigational drug being tested in this study is called ixazomib citrate. Ixazomib citrate is being tested to slow disease progression and improve overall survival in people who have NDMM and who have had any type of positive response to induction therapy followed by HDT and ASCT. This study will look at the effect ixazomib citrate has on the length of time that participants are free of progressive disease (PD) and their overall survival (OS).
The study enrolled 656 participants. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need, or if the disease has progressed and the information is required for planning the next treatment):
- Ixazomib citrate 3 mg for the first 4 cycles, then 4 mg for the remaining 22 cycles
- Placebo (dummy inactive pill) - this is a capsule that looks like the study drug but has no active ingredient.
All participants will be asked to take one capsule on Days 1, 8 and 15 of each 28-day cycle, for up to 26 cycles (approximately 24 months).
This multi-center trial will be conducted globally. The overall time to participate in this study is up to 107 months. Participants will make 28 visits to the clinic during the treatment period and will continue to make visits after treatment has ended. During this initial follow up period, participants will be assessed for disease status with follow up every 12 weeks. After the next line of therapy begins, follow-up will occur every 12 weeks until death or termination of the study.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Adult male or female participants 18 years or older with a confirmed diagnosis of symptomatic multiple myeloma according to standard criteria.
- •Documented results of cytogenetics/ fluorescence in situ hybridization (FISH) obtained at any time before transplant, and International Staging System (ISS) staging at the time of diagnosis available.
- •Underwent standard of care (SOC) induction therapy (induction therapy must include proteasome inhibitor (PI) and/or immunomodulating drugs (IMiD)-based regimens as primary therapy for multiple myeloma), followed by a single autologous stem cell transplant (ASCT) with a high-dose melphalan (200 mg/m^2) conditioning regimen, within 12 months of diagnosis. Vincristine, Adriamycin [doxorubicin], and dexamethasone (VAD) is not an acceptable induction therapy for this trial.
- •Started screening no earlier than 75 days after transplant, completed screening within 15 days, and randomized no later than 115 days after transplant.
- •Must have not received post-ASCT consolidation therapy.
- •Documented response to ASCT (PR, VGPR, CR/stringent complete response [sCR]) according to IMWG criteria.
- •ECOG performance status of 0 to
- •Female participants who:
- •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 through 90 days after the last dose of study drug, AND
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.) Male participants, even if surgically sterilized (ie, status postvasectomy), who:
- •Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
- •Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
- •Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
- •Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
- •Suitable venous access for the study-required blood sampling.
- •Is willing and able to adhere to the study visit schedule and other protocol requirements.
- •Must meet the following clinical laboratory criteria at study entry:
- •Absolute neutrophil count (ANC) ≥ 1,000 per cubic milliliter (/mm^3) and platelet count ≥ 75,000/mm^
- •Platelet transfusions to help participants meet eligibility criteria are not allowed within 3 days before randomization.
- •Total bilirubin ≤ 1.5 * the upper limit of the normal range (ULN).
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 * ULN.
- •Calculated creatinine clearance ≥ 30 milliliter per minute (mL/min).
排除标准
- •Multiple myeloma that has relapsed following primary therapy or is not responsive to primary therapy. For this study, stable disease following ASCT will be considered nonresponsive to primary therapy.
- •Double (tandem) ASCT.
- •Radiotherapy within 14 days before the first dose of study drug.
- •Diagnosed or treated for another malignancy within 5 years before randomization or previously diagnosed with another malignancy with evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
- •Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period.
- •Major surgery within 14 days before randomization.
- •Central nervous system involvement.
- •Infection requiring intravenous (IV) antibiotic therapy or other serious infection within 14 days before randomization.
- •Diagnosis of Waldenstrom's macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
- •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 with strong cytochrome P450 3A (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before randomization in the study.
- •Active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
- •Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens (eg, peripheral neuropathy that is Grade 1 with pain or Grade 2 or higher of any cause).
- •Psychiatric illness/social situation that would limit compliance with study requirements.
- •Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
- •Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
- •Treatment with any investigational products within 60 days before the first dose of the study drug regimen.
研究组 & 干预措施
Placebo
Ixazomib citrate placebo-matching capsules, orally, once on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons.
干预措施: Placebo (Drug)
Ixazomib Citrate
Ixazomib citrate 3 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 1 through 4. Ixazomib citrate 4 mg, capsules, orally, once, on Days 1, 8 and 15 in a 28-day cycle for Cycles 5 through 26 until PD, unacceptable toxicity, or discontinuation for alternate reasons. Participants who have had any dose reductions due to adverse events (AEs) would not be dose escalated.
干预措施: Ixazomib Citrate (Drug)
结局指标
主要结局
Progression Free Survival (PFS)
时间窗: Randomization up to End of treatment (EOT) (24 months); thereafter followed up every 4 weeks (up to 45 months)
PFS was defined as the time from the date of randomization to the date of first documentation of PD, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurred first. PD was defined as ≥25% increase from lowest value in: serum/urine M component; participants without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels must be \>10 milligrams per deciliter (mg/dL); participants without measurable serum, urine M-protein levels and FLC levels, bone marrow plasma cell percent must have been ≥10%; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size increase; hypercalcemia development.
次要结局
- Overall Survival (OS)(Randomization up to end of follow up period (up to 107 months))
- Percentage of Participants With Any Best Response Category Before PD or Subsequent Therapy(Randomization up to EOT (up to 24 months) and thereafter every 4 weeks until initiation of the next line of therapy (up to 107 months))
- Time to Progression (TTP)(Randomization up to PD (up to 107 months))
- Second Progression Free Survival (PFS2)(Randomization up to EOT (24 months); thereafter followed up every 4 weeks until initiation of next-line therapy and then every 12 weeks until second progressive disease (PD2) or death (up to 107 months))
- Time to Start of the Next Line of Therapy(Randomization up to 107 months)
- Time to End of the Next Line of Therapy(Randomization up to 107 months)
- Duration of the Next Line of Therapy(Up to 107 months)
- Percentage of Participants Who Develop a New Primary Malignancy(Up to 107 months)
- Number of Participants With Conversion to Minimal Residual Disease (MRD) Negative(Baseline up to EOT (up to 24 months))
- Number of Participants With Maintenance of MRD Negativity(Up to EOT (up to 24 months))
- Correlation Between MRD Status and Progression Free Survival (PFS)(From randomization up to 107 months)
- Correlation Between MRD Status and Overall Survival (OS)(From randomization up to 107 months)
- OS Benefits in a High-Risk Population(Randomization up to 107 months)
- PFS Benefits in a High-Risk Population(Randomization up to 107 months)
- Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status Score(Baseline up to EOT (up to Month 24))
- Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) or Serious Adverse Events (SAEs)(Up to 107 months)
- Number of Participants With Markedly Abnormal Clinical Laboratory Values Reported as TEAEs(Up to 107 months)
- Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Domain Score(Baseline up to EOT (up to Month 24))
- Plasma Concentration of Ixazomib(Day 1 of Cycle 1: 1 hour and 4 hours post-dose; Predose on Days 8 and 15 of Cycle 1, Days 1 and 8 of Cycle 2, Day 1 of Cycles 3 through 10 (each cycle length= 28 days))
- Time to Resolution of Peripheral Neuropathy (PN) Events(Up to 107 months)
- Time to Improvement of PN Events(Up to 107 months)