Ixazomib In Combination With Cyclophosphamide And Dexamethasone for Newly Diagnosed AL Amyloidosis

This study is a phase 1/2 study to assess safety and hematologic response rate of Ixazomib
(MLN) in combination with Cyclophosphamide (CTX) and Dexamethasone (DEX). This is an open
label multi-center, dose escalation safety study for patients with newly diagnosed AL
Amyloidosis.

A 3+3 design will be utilized to determine the MTD for MLN + CTX + DEX in 28-day treatment
cycle. Treatment cycles will be repeated up to 6 cycles or until disease progression or until
development of significant treatment-related toxicities. A total of up to 30 patients are
planned to enroll into the study, with a maximum of 18 patients in the dose escalation arm
and 18 patients in the MTD expansion arm. The cohort of 6 patients treated at the MTD during
the dose expansion phase will also serve as the initial 6 patients for the expansion Phase II
cohort. These 6 patients will contribute data to both the phase I dose escalation study and
the phase II expansion study. To complete the Phase II cohort, an additional 12 new patients
will need to be enrolled.

MLN will be taken orally on days 1, 8, and 15 at doses of 3 mg or 4 mg. CTX will be taken
orally on the same days with dose escalation from 300 mg up to 500 mg. DEX will be taken
orally on days 1, 8, 15, 22 at 20 mg in the 28-day cycle.

Inclusion Criteria:

- Male or female patients 18 years or older.

- Biopsy-proven diagnosis of 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 defined by serum differential free light chain concentration
(difference between amyloid forming [involved] and non amyloid forming
[uninvolved] free light chain [FLC]) ≥ 50 mg/L).

- Amyloid organ involvement including renal, cardiac, GI and/or nervous system
involvement as well as soft tissue disease

- Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
status 0, 1, or 2.

- Patients must meet the following clinical laboratory criteria:

- Absolute neutrophil count (ANC) ≥1,000/mm3 and platelet count ≥75,000/mm3.

- Hemoglobin ≥ 8.0 g/dL

- Platelet transfusions to help patients meet eligibility criteria are not allowed
within 3 days before study enrollment.

- Total bilirubin ≤ 2 the upper limit of the normal range (ULN) (except patients
with Gilbert's syndrome who must have a total bilirubin of < 3 x ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 ULN.

- Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault Formula).

Exclusion Criteria:

- Female patients who are lactating or have a positive serum pregnancy test during the
screening period.

- Major surgery within 14 days before enrollment.

- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment.

- Evidence of current uncontrolled cardiovascular conditions:

- uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic
congestive heart failure, *unstable angina, or myocardial infarction within the
past 6 months.

Recent history of myocardial infarction in the six months prior to registration

- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of
CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole,
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

- Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive.

- Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

- Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.

- Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of ixazomib including difficulty swallowing.

- Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with early stage prostate cancer, non melanoma skin cancer or
carcinoma in situ of any type are not excluded; patients with malignancies that have
undergone complete resection are not excluded.

- Patient has ≥ Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical
examination during the screening period.

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 21days of the start of this trial and
throughout the duration of this trial.

- New York Heart Association Class III or IV Heart Failure

- NT Pro-BNP > 8500pcg/mL.

- Dialysis dependent renal failure