Trial of Ixazomib, Dexamethasone and Rituximab in Patients With Untreated Waldenstrom's Macroglobulinemia

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational regimen, IDR, to learn whether IDR works in treating
a specific cancer. "Investigational" means that IDR is still being studied and that research
doctors are trying to find out more about it-such as the safest dose to use, the side effects
it may cause, and if IDR is effective for treating different types of cancer. It also means
that the FDA (the U.S. Food and Drug Administration) has not yet approved IDR for use in
participants with your type of cancer.

Ixazomib is a drug that may kill or stop cancer cells from growing by blocking the proteasome
within the cell, which is responsible for degrading or breaking down a variety of proteins.
This type of drug is called a proteasome inhibitor.

Rituximab is a type of protein called an antibody that attacks the cluster of differentiation
20 (CD20), a protein found on B-cells like WM. Rituximab is approved by the FDA for treating
non-Hodgkin lymphoma (NHL). Dexamethasone is a steroid and is similar to the hormones
naturally produced by the adrenal glands; it prevents the release of substances that cause
inflammation. Rituximab and dexamethasone are often used to treat WM, alone or in combination
with other drugs. Combinations with rituximab, dexamethasone and other proteasome inhibitors
have shown good response rates in WM participants. Ixazomib is a proteasome inhibitor; thus
the investigator swill investigate if the combination of Ixazomib, Rituximab, and
Dexamethasone is also active in WM.

In this research study, the investigators are combining a new treatment ixazomib with a
standard regimen, rituximab and dexamethasone, to determine whether this combination (IDR) is
effective and safe for participants with previously untreated WM.

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 the patient
may withdraw consent 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.)

- Clinicopathological diagnosis of WM (Owen 2003), with symptomatic disease meeting
criteria for treatment using consensus panel criteria from the Second International
Workshop on WM (Kyle 2003), and measurable disease, defined as presence of
immunoglobulin M (IgM) paraprotein with a minimum IgM level of >2 times the upper
limit of normal.

- Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

- Patients must meet the following clinical laboratory criteria

- Absolute neutrophil count ≥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 bilirubin ≤1.5 x the upper limit of the normal range (ULN).

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

- Major surgery within 14 days before enrollment.

- 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, with strong inhibitors of
cytochrome P (CYP) 1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use
of Ginkgo biloba or St. John's wort.

- Known hepatitis B or C virus, or HIV infection.

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

- Participation in other clinical trials, including those with other investigational
agents not included in this trial, within 30 days of the start of this trial and
throughout the duration of this trial.