Relapsed or Refractory Systemic Light Chain Amyloidosis
Conditions
Interventions
investigational material(s)
Generic name etc : IXAZOMIB 4 mg + Dexamethasone 20 mg/day
INN of investigational material : Ixazomib, Dexamethasone
Therapeutic category code : 399 Agents affecting metabo
plus dexamethasone 20 mg/day, orally, weekly on Days 1, 8, 15, and 22 of each 28-day cycle
dexamethasone may be increased up to 40 mg/day after 4 weeks, if tolerated. Participants may continue to receive treatment until Progressive Disease (PD) or unacceptable toxicity, whichever comes firs
plus melphalan 0.22 mg/kg, orally, on Days 1-4 every 28 days. c. Dexamethasone 20 mg/day + Cyclophosphamide 500 mg: dexamethasone 20 mg/day, orally, weekly on Days 1, 8, 15 and 22 of each 28-day cycle
plus cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 every 28 days. d. Dexamethasone 20 mg/day + Thalidomide 200 mg/day: dexamethasone 20 mg/day, orally, weekly Days 1, 8, 15 and 22 of each 28-da
plus thalidomide total dose up to 200 mg/ day, orally. e. Dexamethasone 20 mg/day+ Lenalidomide 15 mg/day: dexamethasone 20 mg/day, orally, weekly on Days 1, 8, 15 and 22 of each 28-day cycle
plus lenalidomide 15 mg/day, orally, for 21 days every
Sponsors
Takeda Pharmaceutical Company Limited
Millennium Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female participants 18 years or older. 2. Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis) according to the following standard criteria: a. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an applegreen birefringence b. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary. 3. 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. 4. Objective, measurable major (cardiac or renal) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required): a. 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. b. 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. 5. 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. a. 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.) b. 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 c. Must have recovered (ie, == 1000/mcrL b. Platelet count >= 75,000/mcrL c. Total bilirubin = 80% unconjugated bilirubin and total bilirubin =< 6 mg/dL d. Alkaline phosphatase =< 5 x ULN e. Alanine aminotransferase (
Exclusion criteria
Exclusion criteria: 1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis. 2. Female participants who are lactating, breast feeding, or pregnant. 3. 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. 4. Clinically overt multiple myeloma, according to the International Myeloma Working Group (IMWG) criteria with at least 1 of the following: a. Bone lesions b. Hypercalcemia, defined as a calcium of > 11 mg/dL 5. 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. 6. 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.). 7. 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. 8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection. 9. Psychiatric illness/social situations that would limit compliance with study requirements. 10. Known allergy to boron, MLN9708, any of the study treatments, their analogues, or excipients. 11. 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. 12. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1.Efficacy: Percentage Of Participants With Overall Hematologic Response Timeframe; From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death which occurs first (up to 115 months) Overall Hematologic Response is defined as the percentage of participants with Complete Response (CR), Very Good ISA (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) =50% reduction in dFLC. 2.Efficacy: 2-Year Vital Organ (Heart Or Kidney) Deterioration And Mortality Rate Timeframe; Up to 2 years Cardiac (Heart) deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration will be evaluated by an Adjudication Committee. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1.Percentage Of Participants With Complete Hematologic Response Timeframe; From first dose of study drug until discontinuation of study drug due to PD or unacceptable toxicity, or death whichever occurs first (up to 115 months) Complete Hematologic Response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by the investigator. 2.Overall Survival (OS) Timeframe; From first dose of study drug until discontinuation of study drug due to PD or unacceptable toxicity, or death whichever occurs first (up to 115 months) OS was defined as the time from the date of randomization to the date of death. 3.Progression Free Survival (PFS) Timeframe; From first dose of study drug until discontinuation of study drug due to PD or unacceptable toxicity, or death which occurs first (up to 115 months) PFS was defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurs first according to central laboratory results and ISA criteria as evaluated by the investigator. 4.Hematologic Disease PFS Timeframe; From first dose of study drug until discontinuation of study drug due to PD or unacceptable toxicity, or death which occurs first (up to 115 months) Hematologic disease PFS is defined as the time from the date of randomization to the date of first documentation of hematologic PD or death due to any cause, whichever occurs first. 5.Time To Vital Organ Deterioration And Mortality Rate Timeframe; From randomization to time of vital organ deterioration or death (up to 115 months) Time to vital organ deterioration or death defined as the time from randomization to vital organ deterioration or death, whichever occurs first. 6.Percentage Of Participants With Best Vital Organ (Cardiac And/Or Kidney) Response Timeframe; From first dose of study drug until discontinu | — |
Countries
Japan, Refer to "Other" section
Outcome results
None listed