Venetoclax, MLN9708 (Ixazomib Citrate) and Dexamethasone for the Treatment of Relapsed or Refractory Light Chain Amyloidosis

Inclusion Criteria:

• Histologically-proven systemic anti-light chain amyloidosis (AL) confirmed bypositive Congo red staining with green birefringence on polarized light microscopyand evidence of a measurable clonal disease that requires active treatment. Anunderlying plasma cell disorder can be identified by one of the following: clonalplasma cells in the bone marrow (BM), monoclonal protein in the serum or urine, orabnormal free light chain ratio. For patients who are African-American or males >= 70 years with isolated cardiac involvement, mass spectrometry must be performed toconfirm subtyping

• Presence of t(11;14) by fluorescence in situ hybridization (FISH) on bone marrowbiopsy, either confirmed at screening or documented with a prior biopsy

• Patient requires therapy, as determined by the treating physician, following atleast one line of treatment (No limit on the number of prior treatments)

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of venetoclax in combination with MLN9708 (ixazomib citrate) anddexamethasone in patients < 18 years of age, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,000/mcL. Screening absolute neutrophil count (ANC)should be independent of granulocyte- and granulocyte/macrophage colony stimulatingfactor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for atleast 2 weeks

• Platelets >= 75,000/mcL. Platelet transfusions to help patients meet eligibilitycriteria are not allowed within 2 weeks before study enrollment

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Creatinine Calculated clearance >= 15 mL/min using Cockcroft-Gault equation

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• AL Amyloidosis Cardiac Risk stage I, II or IIIa disease based on the 2013 EuropeanModification of the 2004 Standard Mayo Clinic Staging in patients with advancedcardiac involvement (Dispenzieri et al., 2004; Wechalekar et al., 2013)

• Staging system defined by: NT-proBNP cut off of < 332 pg/mL and troponin Icut-off of < 0.10 ng/mL (in the absence of troponin T, troponin I >= 0.1 ng/mLcan be used) as thresholds for stages I, II and III; NT-proBNP < 8500 pg/ml forstage IIIa

• Stage I, both under threshold;

• Stage I: Zero markers above threshold: NT-proBNP < 332 ng/L AND troponin T (TnT) =< 0.035 ng/mL; NT-proBNP < 332 ng/L AND TnI =< 0.1 ng/mL

• Stage II, either troponin or NT-proBNP (but not both) over threshold;

• Stage II: One marker above threshold: NT-proBNP >= 332 ng/L OR TnT >= 0.035 ng/mL; NT-proBNP >= 332 ng/L OR TnI >= 0.1 ng/mL

• Stage III, both over threshold;

• Stage IIIa, both over threshold but NT-proBNP =< 8500 pg/ml

• Stage IIIa: Two markers above threshold: NT-proBNP >= 332 ng/L BUT =< 8,500 ng/L AND TnT >= 0.035 ng/mL; NT-proBNP >= 332 ng/L BUT =< 8,500 ng/LAND TnI >= 0.1 ng/mL

• Stage IIIb: Two markers above threshold: NT-proBNP > 8,500 ng/L AND TnT >= 0.035 ng/mL; NT-proBNP > 8,500 ng/L AND TnI >= 0.1 ng/mL

• Life expectancy >= 3 months

• Plasma cell burden =< 60%

• Absence of bone lesions and other end organ disease consistent with multiple myeloma (patients with plasma cell burden between 10 and 60% without end organ disease canbe included)

• Measurable disease of AL amyloidosis as defined by at least one of the following: 1)serum or urine monoclonal protein >= 500 mg/dL by protein electrophoresis, or 2)serum free light chain >= 20 mg/L with an abnormal kappa:lambda ratio or thedifference between involved and uninvolved free light chains (dFLC) >= 20 mg/L

• It is not known what effects MLN9708 (ixazomib citrate), venetoclax, anddexamethasone have on human pregnancy or development of the embryo or fetus.Therefore, female patients participating in this study should avoid becomingpregnant, and male patients should avoid impregnating a female partner.Nonsterilized female patients of reproductive age group and male patients should useeffective methods of contraception through defined periods during and after studytreatment as specified below.

• Female patients must meet 1 of the following:

• Postmenopausal for at least 1 year before the screening visit, or

• Surgically sterile, or

• If they are of childbearing potential, agree to practice 2 effectivemethods of contraception from the time of signing of the informed consentform through 90 days after the last dose of study drug, or

• Agree to practice true abstinence, when this is in line with the preferredand usual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods] and withdrawal are notacceptable methods of contraception)

• Male patients, even if surgically sterilized (i.e., status postvasectomy) mustagree to 1 of the following:

• Practice effective barrier contraception during the entire study treatmentperiod and through 90 days after the last dose of study drug, or

• Agree to practice true abstinence, when this is in line with the preferredand usual lifestyle of the subject. (Periodic abstinence [e.g., calendar,ovulation, symptothermal, postovulation methods for the female partner]and withdrawal are not acceptable methods of contraception)

• Left ventricular ejection fraction >= 35% by echocardiogram.

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who have had major surgery or radiotherapy within 14 days prior to enteringthe study. If the involved radiotherapy field is small, 7 days will be considered asufficient interval between treatment and administration of the MLN9708 (ixazomibcitrate)

• Patients who have had anti-plasma cell therapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia

• Patients who are receiving any other investigational agents, within 30 days of thestart of this trial and throughout the duration of this trial

• Patients with central nervous system involvement

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to venetoclax, MLN9708 (ixazomib citrate) (including boron orboron-containing products) or dexamethasone

• Strong or moderate CYP3A inhibitors (e.g., erythromycin, ciprofloxacin, diltiazem,fluconazole, verapamil), or strong CYP3A inducers (e.g., carbamazepine, phenytoin,rifampin, St. John's wort), or moderate CYP3A inducers (e.g., bosentan, efavirenz,etravirine) should be avoided

• Venetoclax should be administered using caution with substrates or inhibitors ofP-glycoprotein (P-gp)

• Patients with uncontrolled intercurrent illness including, but not limited to:ongoing or active serious or systemic infection (within 14 days prior to studyenrollment), active hepatitis B or C virus infection, hypertension, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, ormyocardial infarction (within the past 6 months)

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Female patients who are lactating or have a positive serum pregnancy test during thescreening period are excluded from this study because MLN9708 (ixazomib citrate) isa proteasome inhibitor with the potential for embryo-lethal effects, and an unknownbut potential risk for adverse events in nursing infants secondary to treatment ofthe mother with MLN9708 (ixazomib citrate). Patients must stop breastfeeding whileon MLN9708 (ixazomib citrate) and until 90 days have passed since their last dose.These potential risks may also apply to other agents used in this study

• Known gastrointestinal disease or gastrointestinal procedure that could interferewith the oral absorption or tolerance of MLN9708 (ixazomib citrate), includingdifficulty swallowing

• Peripheral neuropathy that is >= grade 3, or grade 2 with pain on clinicalexamination during the screening period

• Patients that have previously been treated with MLN9708 (ixazomib citrate). Patientswho have received prior treatment with venetoclax

• Patients without measurable disease by serum free light chain, serum m-spike orurine monoclonal protein

• Patients with New York Heart Association classification III/IV. Patients withadvanced cardiac amyloidosis, Mayo stage IIIB based on European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement withNT-Pro BNP > 8500 pg/mL (Wechalekar et al., 2013)

• Patients with grade 3 or worse diarrhea