UARK 2014-14: Phase II Prospective Evaluation of Bone Remodeling During Ixazomib Treatment

This is a phase II study designed to examine the bone anabolic effect of the next generation
proteasome inhibitor, ixazomib, in relapsed/refractory myeloma patients. Treatment consists
of Ixazomib 4 mg on days 1, 8, 15, 22 of a 28 day cycle, for a maximum of 6 cycles.
Determination of relapsed/refractory disease as an entry criterion may be based on patient
data obtained during or following the patient's most recent prior antineoplastic therapy.
Treatment periods will be defined as 28-day cycles. Patients will be seen at regular
intervals while they are participating in the study.

Inclusion Criteria:

Male or female patients 18 years or older.

- 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be withdrawn by the patient at any time without prejudice to future medical care.

- Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR Are surgically
sterile, OR 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 form through
90 days after the last dose of study drug, AND Agree to practice true abstinence when this
is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg,
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception.)

Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one
of the following:

Agree to practice effective barrier contraception during the entire study treatment period
and through 90 days after the last dose of study drug, OR Agree to practice true abstinence
when this is in line with the preferred and usual lifestyle of the subject. (Periodic
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal
are not acceptable methods of contraception.)

- Patients must have a diagnosis of relapsed/refractory multiple myeloma and must have
received at least one line of prior therapy.

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

Total bilirubin1.5 the upper limit of the normal range (ULN). Alanine aminotransferase
(ALT) and aspartate aminotransferase (AST) 3 ULN. Calculated creatinine clearance 30
mL/min.

Exclusion Criteria:

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

- Failure to have fully recovered (ie, Grade 1 toxicity) from the reversible effects of
prior chemotherapy.

- Major surgery within 14 days before enrollment.

- Radiotherapy within 14 days before enrollment. If the involved field is small (in the
opinion of the enrolling investigator), 7 days will be considered a sufficient
interval between treatment and administration of the ixazomib.

- Patients who have non-myeloma related bone disease that will interfere with the
interpretation of the bone-related blood and radiology assessments, including Paget's
disease, Rickets, Osteomalacia, and any other metastatic bone cancer.

- History of myeloma-related central nervous system involvement.

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

- Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.

- 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, known 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 history of 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 non-melanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection.

- 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 21 days of the start of this trial and
throughout the duration of this trial.

- Patients who have taken bisphosphonate or RANK Ligand Inhibitor within 3 weeks from
screening.