Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis
Condition: Relapsed or Refractory Systemic Light Chain Amyloidosis
MeSH terms: Amyloidosis
Intervention: IXAZOMIB; Dexamethasone; Melphalan; Cyclophosphamide; Thalidomide; Lenalidomide
Intervention description: Ixazomib capsules; Dexamethasone tablets; Melphalan tablets; Cyclophosphamide tablets; Thalidomide capsules; Lenalidomide capsules
Intervention MeSH terms: Thalidomide; Dexamethasone; Cyclophosphamide; Melphalan; Lenalidomide; Ixazomib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 177.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MLN9708; Amyloidosis; Light Chain; IXAZOMIB; Tourmaline AL1; Drug Therapy

Summary:

      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.
    

Eligibility 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:

               1. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo
                  red staining with exhibition of an apple-green birefringence

               2. 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):

               1. 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.

               2. 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.

               1. 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.)

               2. 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

               3. Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status)
                  from the reversible effects of prior therapy

               4. 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.

          6. 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):

               1. Stage 1: both NT-proBNP and troponin T under threshold

               2. Stage 2: either NT-proBNP or troponin T (but not both) over threshold;

               3. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP < 8000
                  pg/mL)

          7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.

          8. Clinical laboratory values:

               1. Absolute neutrophil count ≥ 1000/µL

               2. Platelet count ≥ 75,000/µL

               3. 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

               4. Alkaline phosphatase ≤ 5 x ULN

               5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN

               6. Calculated creatinine clearance ≥ 30 mL/min

          9. Female participants who:

               1. 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

               2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, OR

               3. 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:

               1. Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug, AND

               2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention
                  program, if applicable, OR

               3. 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.)

         10. 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.

        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:

               1. Bone lesions

               2. 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.