Ixazomib & Rituximab After Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma in Remission

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose and assess the safety of ixazomib when
administered as post-transplant maintenance in mantle cell lymphoma and to evaluate the
safety of rituximab in combination with the recommended phase II dose (RP2D) of ixazomib.
(Phase I)

II. To assess preliminary evidence of efficacy of ixazomib in combination with rituximab when
administered as post-transplant maintenance in mantle cell lymphoma. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate for preliminary evidence of efficacy of ixazomib (+/- rituximab) maintenance
therapy in patients with mantle cell lymphoma undergoing autologous stem cell transplant in
first partial or complete remission. (Phase I)

II. To evaluate for preliminary evidence of efficacy of ixazomib (+/- rituximab) maintenance
therapy in patients with mantle cell lymphoma who have a complex karyotype and other
high-risk cytogenetic or clinical markers. (Phase I)

III. To evaluate toxicities associated with prolonged administration of ixazomib maintenance
therapy in patients with mantle cell lymphoma (MCL). (Phase I)

IV. To evaluate the rate of minimal residual disease (MRD) in patients who have completed an
autologous transplant for mantle cell lymphoma and to assess the impact of MRD on outcomes
for patients receiving maintenance therapy. (Phase I)

V. To evaluate efficacy of ixazomib with rituximab maintenance therapy in patients with MCL
who undergo autologous stem cell transplantation in first remission who have a complex
karyotype and/or additional high risk cytogenetic or clinical features at diagnosis. (Phase
II)

VI. To further evaluate safety and toxicity of prolonged administration of ixazomib. (Phase
II)

VII. To evaluate long-term disease-related and survival outcomes for patients with MCL who
receive post-transplant maintenance therapy with ixazomib with rituximab. (Phase II)

VIII. To evaluate the rate of minimal residual disease (MRD) in patients who have completed
an autologous transplant for mantle cell lymphoma and to assess the impact of MRD on outcomes
for patients receiving maintenance therapy. (Phase II)

TERTIARY OBJECTIVES:

I. To evaluate the prognostic value of pre-transplant positron emission tomography
(PET)/computed tomography (CT) in mantle cell lymphoma.

II. To evaluate the ability of the single nucleotide polymorphism (SNP) array to identify
high-risk cytogenetic features in patients with MCL.

III. To evaluate the impact of ixazomib maintenance (+/- rituximab) on immunoglobulin levels
for patients completing autologous stem cell transplantation for mantle cell lymphoma.

OUTLINE: This is a phase I, dose-escalation study of ixazomib followed by a phase II study.

Beginning between 70-180 days after stem cell transplant, patients receive ixazomib orally
(PO) on days 1, 8, and 15, and rituximab intravenously (IV) (or subcutaneously [SC] after
first dose if deemed appropriate) on day 1 of courses 1, 3, 5, 7, and 9. Treatment repeats
every 28 days for up to 10 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2
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 [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 mantle cell lymphoma confirmed at diagnosis by one
of the following:

- t(11;14) detected by fluorescence in situ hybridization (FISH), conventional
cytogenetics, or other molecular evaluation

- Expression of cyclin D1 confirmed by immunohistochemistry.

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

- Patients must have completed an autologous stem cell transplant after their first
course of treatment; patients who have relapsed or progressed at any time prior to
transplant are not eligible.

- Patients must not have experienced confirmed progressive disease since the time of
their transplant.

- 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. Patients may receive growth factor support prior to
initiating therapy but must remain off of growth factor for at least 7 days before
starting therapy and must meet eligibility on cycle 1, day 1. Patients who complete
the consent process but do not meet hematologic eligibility within 30 days may be
re-consented and enrolled on study if they ultimately do meet eligibility requirements
before day +180. No patients may initiate therapy after day +180 and they must meet
all remaining eligibility criteria.

- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN) except for
previously documented Gilbert's disease, defined as a mild unconjugated
hyperbilirubinemia with no other identifiable cause and bilirubin values < 6 mg/dL;
patients with hyperbilirubinemia secondary to presumed Gilbert's disease who are being
considered for enrollment in the study MUST have a fractionated bilirubin included in
their screening labs when determining eligibility.

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

- Calculated creatinine clearance ≥ 30 mL/min using Cockcroft-Gault formula.

- Note: Patients are expected to initiate therapy as close to day +100 as possible. No
patient may initiate therapy before day +70 and initiation of therapy beyond day +130
is allowed ONLY for patients who meet all eligibility criteria except for hematologic
parameters, in which case patients may be delayed until their hematologic laboratories
meet criteria but no later than day +180. Regardless of the time of therapy
initiation, patients must meet all eligibility criteria and must have completed all
consent documentation and screening procedures within the specified window.

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, except for laboratory abnormalities which are addressed above.

- Major surgery within 14 days before enrollment.

- Radiotherapy within 14 days before enrollment; if the involved field is small, 7 days
will be considered a sufficient interval between treatment and administration of the
ixazomib.

- Central nervous system involvement with lymphoma at any time in the patient's history;
intrathecal prophylaxis during induction is allowed as long as active disease has not
been identified.

- Infection requiring intravenous 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; patients
experiencing an isolated cardiac complication at the time of transplant who have been
evaluated by cardiology and remained stable for at least 60 days are eligible.

- Systemic treatment, within 14 days before the first dose of ixazomib, with strong
cytochrome P450, family 3, subfamily A (CYP3A) inducers (rifampin, rifapentine,
rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.

- Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive. Patients who have previously tested
positive for hepatitis B core antibody may be eligible if they are confirmed to NOT
have active disease and are on appropriate anti-viral therapy. No additional hepatitis
or HIV testing is required for patients who have been evaluated during their induction
and/or pre-transplant work-up and have had no clinical evidence of HIV, hepatitis B or
hepatitis C since their last evaluation.

- 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. Patients with a prior reaction to rituximab are
permitted if the investigator feels that this reaction is manageable with standard
supportive care measures and would otherwise be comfortable administering rituximab
outside of the clinical trial setting.

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib including difficulty swallowing; patients with
known GI involvement with mantle cell lymphoma who have no clinical evidence of active
disease at the time of enrollment are eligible.

- 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, carcinoma in situ of any type, or low
risk cervical cancer are not excluded if they have undergone complete resection and
are deemed free of disease by their treating physician; patients with low risk
prostate cancer who are under observation are eligible if their urologist or
oncologist does not expect them to require therapy within 1 year.

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

- Receipt of therapy on a clinical trial, including investigational and
non-investigational agents not included in this trial, within 30 days of the start of
this trial and throughout the duration of this trial; participation on non-therapeutic
clinical studies is allowed, and patients who participated on a clinical trial for
induction and/or transplant but who have completed the prescribed therapy course for
that study and have been off therapy for at least 30 days are eligible.

- Prior exposure to ixazomib; however, prior bortezomib exposure is allowed.

- Patients with any history of relapsed/refractory disease, or who have progressed at
any time since beginning induction therapy are not eligible; patients who have
evidence of residual disease by FISH, cytogenetics, SNP array, or flow cytometry
without any measurable nodal disease or morphologic evidence of disease in the bone
marrow or peripheral blood are eligible.