Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Conditions
Interventions
Product Name: Ixazomib Capsules, 4.0mg
Product Code: MLN9708
Pharmaceutical Form: Capsule
INN or Proposed INN: ixazomib citrate
CAS Number: 1239908-20-3
Current Sponsor code: MLN9708
Other descriptive
Sponsors
Millennium Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female patients 18 years or older. 2. Biopsy-proven diagnosis of 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 apple-green birefringence b. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary (see Section 15.1) 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 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. Patient must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed patients in the future, at some time point after the first IA. In that case, the patient 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 patient, the patient may be refractory to an agent/s listed within the list of offered treatment choices c. Must have recovered (ie, = Grade 1 toxicity or patient’s baseline status) from the reversible effects of prior therapy d. If a patient has received a transplant as his/her first-line therapy, he/she must be at least 3 months posttransplantation and recovered from the side effects of the stem cell transplant 6. Patient must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by NT-proBNP cut off of 80% unconjugated bilirubin and total bilirubin <= 6 mg/dL d. Alkaline phosphatase = 5 x ULN, e. ALT or AST =3 x ULN f. Calculated creatinine clearance = 30 mL/min 9. Female patients who: a. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same tim
Exclusion criteria
Exclusion criteria: Prospective patients will be excluded from this study if they meet ANY of the following criteria: 1. Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis. 2. Female patients who are lactating, breastfeeding, or pregnant. 3. Medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure (Section 15.6), 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 IMGW 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 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, patients may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent [Section 15.7]) 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 patient 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 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 before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients 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 |
|---|---|
| Main Objective: ? To determine whether dexamethasone plus ixazomib improves hematologic response (PR + VGPR + CR) versus a physician’s choice of a chemotherapy regimen as selected from the list of offered treatment options in patients diagnosed with relapsed or refractory AL amyloidosis. ? To determine whether dexamethasone plus ixazomib improves 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician’s choice of a chemotherapy regimen as selected from the list of offered treatment options in patients diagnosed with relapsed or refractory AL amyloidosis. Cardiac 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.;Secondary Objective: Key secondary objectives: ? To determine OS ? To determine the complete hematologic response rate The protocol provides details of further secondary objectives.;Primary end point(s): ? Overall hematologic (CR + VGPR + PR) response rate based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as evaluated by an Adjudication Committee (AC) ? 2-year vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac 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 AC.;Timepoint(s) of evaluation of this end point: Timepoints are also assessed at screening ?Serum M-protein/FLC: D1 until PD, EOT; every 6wks during PFS ?Urine M-protein: C1D1, as clinically indicated, EOT; every 12wks during PFS ?IgG/immunofixation: PD, EOT, as clinically indicated ?Skeletal survey: as clinically indicated ?Bone marrow: as clinically indicated, confirm CR ?Total p | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The key secondary endpoints are: ? Complete hematologic response rate (CR) according to central laboratory results and ISA criteria as evaluated by an AC ? OS, measured as the time from randomization to the date of death Other secondary endpoints are: ? PFS, defined as the time from the date of randomization to the date of first documentation of disease progression (hematologic PD or major organ progression [specifically involvement of heart or kidney] whichever occurs first) according to central laboratory results and ISA criteria as evaluated by an AC, or death due to any cause, whichever occurs first ? Hematologic disease PFS, defined as the time from the date of randomization to the date of first documented hematologic disease progression according to central laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first ? Time to vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation. ? Best response in the vital organs allowed at study entry (heart and kidney) according to central laboratory results and International Society of Amyloidosis criteria as evaluated by an AC. ? Vital organ PFS, defined as the time from the date of randomization to the date of first documentation of progression of vital organ (that is, heart or kidney) according to central laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first ? Duration of hematologic response, measured as the time from the date of first documentation of hematologic response to the date of first documented hematologic disease progression, respectively according to central laboratory results and ISA criteria as determined by an AC ? Adverse events (AEs), serious adver | — |
Countries
Australia, Brazil, Canada, Czech Republic, Denmark, France, Germany, Greece, Israel, Italy, Korea, Republic of, Netherlands, Spain, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactDrug Information Call Center
Millennium Pharmaceuticals, Inc.
Outcome results
None listed