A Phase 3, Randomized, Controlled, Open-label, Multicenter, Safety and Efficacy Study of Dexamethasone Plus MLN9708 or Physicians Choice of Treatment Administered to Patients With Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 177
- 试验地点
- 66
- 主要终点
- Percentage of Participants With Overall Hematologic Response
研究概览
简要总结
The purpose of this study is to provide continued access of ixazomib and/or other study medications and to continue collecting relevant safety data to monitor participant's safety, determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.
详细描述
The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.
The study will enroll approximately 177 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:
- IXAZOMIB 4 mg plus Dexamethasone 20 mg
- Physician's choice: Participants will receive one of the following treatment options as selected by the physician:
- Dexamethasone 20 mg
- Dexamethasone 20 mg + Melphalan 0.22 mg/kg
- Dexamethasone 20 mg + Cyclophosphamide 500 mg
- Dexamethasone 20 mg + Thalidomide 200 mg
- Dexamethasone 20 mg + Lenalidomide 15 mg
- All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.
This multi-center trial will be conducted worldwide. The overall time to participate in this study is 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.
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
- •Male or female participants 18 years or older.
- •Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis) according to the following standard criteria:
- •Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence
- •If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary.
- •Measurable disease as defined by serum differential free light chain concentration (dFLC, difference between amyloid forming [involved] and nonamyloid forming [uninvolved] free light chain [FLC]) ≥ 50 mg/L.
- •Objective, measurable major (cardiac or renal) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
- •Cardiac involvement is defined as the presence of a mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of other potential causes of left ventricular hypertrophy (controlled hypertension is allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy in the presence of clinical or laboratory evidence of involvement. If there is isolated cardiac involvement, then typing of amyloid deposits is recommended.
- •Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
- •Note: Amyloid involvement of other organ systems is allowed, but not required.
- •Must be relapsed or refractory after 1 or 2 prior therapies. For this protocol, relapsed is defined as progressive disease (PD) documented more than 60 days after last dose; refractory is defined as documented absence of hematologic response or hematologic progression on or within 60 days after last dose of prior therapy.
- •Participant must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed participants in the future, at some time point after the first interim analysis (IA). In that case, the participant may not be refractory to proteasome inhibitor therapy.)
- •Given that the physician may select from an offered list of regimens to treat a specific participant, the participant may be refractory to an agent/s listed within the list of offered treatment choices
- •Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status) from the reversible effects of prior therapy
- •If a participant has received a transplant as his/her first-line therapy, he/she must be at least 3 months post transplantation and recovered from the side effects of the stem cell transplant.
- •Must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by N-terminal proBNP [NT-proBNP] cut-off of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as thresholds):
- •Stage 1: both NT-proBNP and troponin T under threshold
- •Stage 2: either NT-proBNP or troponin T (but not both) over threshold;
- •Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP < 8000 pg/mL)
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤
- •Clinical laboratory values:
- •Absolute neutrophil count ≥ 1000/µL
- •Platelet count ≥ 75,000/µL
- •Total bilirubin ≤ 1.5 upper limit of normal (ULN), except for participants with Gilbert's syndrome as defined by > 80% unconjugated bilirubin and total bilirubin ≤ 6 mg/dL
- •Alkaline phosphatase ≤ 5 x ULN
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN
- •Calculated creatinine clearance ≥ 30 mL/min
- •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 treatment, 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 line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.).
- •Male participants, even if surgically sterilized (ie, status post vasectomy), 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 line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] 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.
排除标准
- •Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis.
- •Female participants who are lactating, breast feeding, or pregnant.
- •Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.
- •Clinically overt multiple myeloma, according to the International Myeloma Working Group (IMWG) criteria with at least 1 of the following:
- •Bone lesions
- •Hypercalcemia, defined as a calcium of > 11 mg/dL
- •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.
- •Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, participants may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent) if they are being given for disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
- •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.
- •Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.
- •Psychiatric illness/social situations that would limit compliance with study requirements.
- •Known allergy to boron, MLN9708, any of the study treatments, their analogues, or excipients.
- •Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
- •Diagnosed or treated for another malignancy within 3 years (or 5 years for participants in France) before study enrollment or previously diagnosed with another malignancy and have any 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.
研究组 & 干预措施
Arm A: Ixazomib + Dexamethasone
Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.
干预措施: IXAZOMIB (Drug)
Arm A: Ixazomib + Dexamethasone
Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.
干预措施: Dexamethasone (Drug)
Arm B: Dexamethasone + Melphalan
Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.
干预措施: Dexamethasone (Drug)
Arm B: Dexamethasone + Melphalan
Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.
干预措施: Melphalan (Drug)
Arm B: Dexamethasone + Cyclophosphamide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months.
干预措施: Dexamethasone (Drug)
Arm B: Dexamethasone + Cyclophosphamide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months.
干预措施: Cyclophosphamide (Drug)
Arm B: Dexamethasone + Thalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.
干预措施: Dexamethasone (Drug)
Arm B: Dexamethasone + Thalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.
干预措施: Thalidomide (Drug)
Arm B: Dexamethasone + Lenalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
干预措施: Dexamethasone (Drug)
Arm B: Dexamethasone + Lenalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Percentage of Participants With Overall Hematologic Response
时间窗: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Overall hematologic response was defined as the percentage of participants with complete response (CR), very good partial response (VGPR) and partial response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an adjudication committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of free light chain (FLC) ratio. VGPR: differential free light chain (difference between involved and uninvolved FLC levels; dFLC) \< 40 mg/L. PR: ≥50% reduction in dFLC. Percentages were rounded off to the nearest decimal.
2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
时间窗: Up to 2 years
Cardiac (Heart) deterioration was defined as the need for hospitalization for heart failure. Kidney deterioration was defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration was evaluated by an adjudication committee. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
次要结局
- Percentage of Participants With Complete Hematologic Response(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Overall Survival(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Progression Free Survival (PFS)(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Hematologic Disease Progression Free Survival(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate(From randomization to time of vital organ deterioration or death (up to 115 months))
- Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Vital Organ Progression Free Survival(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Duration of Hematologic Response(From time of first documented response to disease progression (up to 115 months))
- Number of Participants With Serious Adverse Events (SAEs)(From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months))
- EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score(At Week 28 of the OS follow-up)
- Time To Treatment Failure (TTF)(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))
- Time To Subsequent Anticancer Treatment(From first dose of study drug until subsequent anticancer treatment (up to 115 months))
- Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up(Baseline, Week 28 of the PFS Follow-up)
- Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up(Baseline, Week 28 of the PFS Follow-up)
- Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up(Baseline, Week 28 of the PFS Follow-up)
- Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up(Baseline, Week 28 of the PFS Follow-up)
- Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score(At Week 28 of the OS follow-up)
- Plasma Concentration of Ixazomib(Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days))
- Number of Hospitalizations(From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months))