Ixazomib Citrate and Rituximab in Treating Patients With Indolent B-cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To assess the efficacy of ixazomib (ixazomib citrate) as monotherapy in untreated indolent
B-cell non-Hodgkin lymphoma (B-NHL) based on overall response rate.

SECONDARY OBJECTIVES:

I. To evaluate efficacy parameters including the duration of response (DOR), progression-free
survival (PFS), time to next therapy (TNT), and complete response rate (CR) of ixazomib in
untreated indolent B-NHL.

II. To evaluate the safety and tolerability of ixazomib in subjects with B-NHL.

III. To evaluate the safety and tolerability of ixazomib plus rituximab in subjects with
B-NHL.

IV. To evaluate the efficacy parameters including overall response rate (ORR), DOR, TNT, PFS,
and CR of the combination of rituximab with ixazomib.

TERTIARY OBJECTIVES:

I. To evaluate clinical and biological prognostic and predictive biomarkers relative to
treatment outcomes of ixazomib in indolent B-NHL.

OUTLINE:

Patients receive ixazomib citrate orally (PO) once weekly every 4 weeks. Upon completion of 6
courses of ixazomib citrate therapy, patients also receive rituximab intravenously (IV) once
weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3
months for 3 years.

Inclusion Criteria:

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be withdrawn by the patient at any time without prejudice to future medical care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

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject; (periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Male patients, even if surgically sterilized (i.e., 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 [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods
of contraception)

- Patients must have a diagnosis of one of the following B-NHL malignancies: chronic
lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), follicular lymphoma
(FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom
macroglobulinemia (WM)/ lymphoplasmacytic lymphoma (LPL); patients with mucosa
associated lymphoid tissue (MALT) subtype of MZL may have relapsed or refractory
disease after a course of antibiotic therapy; otherwise, patients will not have
received standard systemic treatment for their B-NHL before the time of study
enrollment; standard systemic therapy is defined by including any of the following
agents, representing a comprehensive list of recommended front-line agents used in the
treatment of B-NHL: cytotoxic chemotherapies (bendamustine, cyclophosphamide,
doxorubicin, vincristine, chlorambucil, cytarabine, gemcitabine, platinum drugs,
etoposide); anti-CD20 antibodies (obinutuzumab, ofatumumab, rituximab); lenalidomide;
ibritumomab tiuxetan; proteasome inhibitors (bortezomib, carfilzomib); tyrosine kinase
inhibitors (ibrutinib, acalabrutinib, idelalisib); alemtuzumab; corticosteroids unless
given for an indication other than treating the B-NHL; or other therapy as determined
by the principal investigator (PI)

- Disease: CLL/SLL; Criteria for diagnosis: histopathologic or flow cytometric
confirmation

- Disease: FL; Criteria for diagnosis: histopathologic confirmation

- Disease: MZL; Criteria for diagnosis: histopathologic confirmation

- Disease: MCL; Criteria for diagnosis: histopathologic confirmation

- Disease: WM/LPL; Criteria for diagnosis: Per World Health Organization (WHO)
criteria

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

- Absolute neutrophil count (ANC) >= 1,000/mm^3 without growth factor support

- Platelet count >= 100,000/mm^3 or >= 75,000/mm^3 if thrombocytopenia is attributed to
B-NHL (involvement of bone marrow or due to splenomegaly or immune thrombocytopenic
purpura); 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

- Patients are required to meet criteria for initiation of therapy for their B-NHL
according to published guidelines by the National Comprehensive Cancer Network (NCCN)

- Patients must have measurable disease defined by at least one of the following
criteria:

- Lesions greater than 1.5 cm that can be accurately measured in two dimensions by
computed tomography (CT) (preferred), or magnetic resonance imaging (MRI), and
are not included in any prior field of radiation given to treat B-NHL

- In patients with CLL, circulating lymphocytes >= 5,000 / mm^3

- In patients with WM/LPL, measurable serum monoclonal immunoglobulin M (IgM)

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

- Known 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, cardiac arrhythmias, or congestive heart failure, and 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 cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2)
(fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of cytochrome P450, family
3, subfamily A (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

- Known ongoing or known 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 ixazomib, its analogues, or excipients in the various formulations of
ixazomib

- 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 (> 2 years before study enrollment) with another malignancy and
have any evidence of residual disease that is symptomatic or requiring treatment;
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 2 peripheral neuropathy, or grade 1 with pain on clinical
examination during the screening period

- Participation in other clinical trials 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 may not have impending organ compromise from disease as assessed by their
treating physician

- Prior treatment of B-NHL with radiation therapy, non-standard systemic therapy, or
antibiotics (in cases of MZL) within 21 days of the first dose of ixazomib